ES2217279T3 - COMPOUNDS WITH ANTIHIPERTENSIVE, CARDIOPROTECTOR, ANTI-ISCHEMICAL AND ANTILIPOLITIC PROPERTIES. - Google Patents

Abstract

REFERENCE IS MADE TO ADENOSINE DERIVATIVES AND ANALOGS THAT HAVE ADENOSINE AGONIST ACTIVITY AND HAVE UTILITY AS ANTIHIPERTENSIVE AGENTS, CARDIOPROTECTORS, ANTISCHEMICALS, AND ANTILIPOLITICS, TO PHARMACEUTICAL COMPOUNDS THAT INCLUDE THE USE OF THE SUPPLY OF THE CONTRACT, MIOCARDIO, THE IMPROVEMENT OF ISCHEMICAL INJURIES DERIVED FROM MYOCARDIUM INFARTS THAT FOLLOW THE MIOCARDIO ISCHEMIA; IN THE TREATMENT OF HYPERLIPIDEMIA AND HYPERCHOLESTORLEMIA; AND TO METHODS AND MEANS USED IN THE PREPARATION OF THE MENTIONED COMPOUNDS.

Description

Compound with antihypertensive properties, cardioprotective, anti-ischemic and antilipolytics

This request is a continuation request of US Pat. No. 5,561,134 issued October 1, 1996, which is a continuation request in part of the number of US application series 08 / 229,882 filed on April 19, 1994, now abandoned, which is a continuation request in part of US Pat. No. 5,364,862 issued on 15 November 1994, which is a continuation in part of the number of US application series 07 / 587,884 filed on 25 September 1990, now abandoned.

Background of the invention 1. Field of the invention

This invention relates to derivative compounds of adenosine and its analogues, to the pharmaceutical compositions that contain such compounds, for use in the prevention of injury ischemic, and its use as antilipolytic agents that reduce plasma lipid levels, triglyceride levels serum, and plasma cholesterol levels, and to methods e intermediates used in the preparation of such compounds.

Hypertension

Hypertension, blood pressure disease high, affects a substantial number of the human population. The Consequences of persistent hypertension include vascular damage to the ocular, renal, cardiac and cerebral systems, and the risk of these complications increase with increasing tension arterial. The basic factors that control blood pressure are cardiac output and peripheral vascular resistance, this being the predominant common mechanism, which is controlled by various influences The sympathetic nervous system regulates resistance peripheral vascular through direct effects on alpha and beta adrenergic receptors, as well as through effects indirect on the release of renin. The treatment Pharmacological addresses specific components of these systems blood pressure regulators, with different mechanisms of action that define the different classes of drugs, which include diuretics, beta adrenergic receptor antagonists (beta blockers), angiotensin converting enzyme inhibitors (RCT) and calcium channel antagonists.

Thiazide diuretics are used in the hypertension to reduce peripheral vascular resistance by medium of its effects on the excretion of sodium and water. This class of drugs includes hydrochlorothiazide, chlorothiazide, methylchlorothiazide and cyclothiazide, as well as related agents indapamide, metolazone and chlorthalidone. Although before it was believed that the beta blocker mechanism of action was the blockage of the subtype of beta1 adrenergic heart receptor to reduce heart rate and cardiac output, beta blockers more Recent with intrinsic sympathomimetic activity (ISA), which include pindolol, acebutolol, penbutolol and carteolol, they are so effective as non-ISA beta blockers, and cause a reduction lower in heart rate and cardiac output. Others Postulated mechanisms for these drugs include inhibition of the release of renin, a central effect, and an effect on presynaptic beta adrenergic receptors that result norepinephrine release inhibition. Beta metoprolol cardioselective blockers (Lopressor-Geigy), acebutolol (Sectral-Wyeth) and atenolol (Tenormin-ICI), at low doses, have an effect higher on beta1 adrenergic receptors than on subtypes of beta2 adrenergic receptors located in the bronchial tubes and blood vessels Non-selective beta blockers they act on both subtypes of beta adrenergic receptors, and include propranolol (Inderal-Ayerst), timolol (Blocadren-Merck), nadolol (Corgard-Squibb), pindolol (Visken-Sandoz), penbutolol (Levatol-Hoechst-Roussel) and carteolol (Cartrol-Abbott). The adverse effects of beta blockers include asymptomatic bradycardia, exacerbation  of congestive heart failure, abnormalities gastrointestinal, respiratory tract resistance increased, masked symptoms of hypoglycemia and depression. They can cause elevation of serum triglycerides and can lower high density lipoprotein cholesterol.

ACE inhibitors prevent the formation of angiotensin II and inhibit the degradation of bradykinin. The angiotensin II is a potent vasoconstrictor and also stimulates the aldosterone secretion When producing the system crash renin-angiotensin-aldosterone, these agents decrease peripheral vascular resistance as well such as sodium and water retention. In addition, ACE inhibitors increase levels of bradykinin and prostaglandins, endogenous vasodilators. Captopril (Capoten-Squibb) and Enalapril (Vasotec-Merck) are the main ACE inhibitors. Adverse effects of ACE inhibitors include antemas, taste disturbance, proteinuria and neutropenia.

Calcium channel antagonists reduce the calcium entry into vascular smooth muscle cells and produce systemic vasodilation, which results in its effect antihypertensive Other effects of channel antagonists Calcium include interference with the action of angiotensin II and alpha2 adrenergic receptor block, which can be added to its antihypertensive effects. Channel antagonists Calcium do not have adverse metabolic and pharmacological effects of thiazides or beta blockers, and can be useful for this in patients with diabetes, peripheral vascular disease or chronic obstructive pulmonary disease. Two channel antagonists of calcium, Verapamil and Diltiazem, have serious effects Cardiovascular events on cardiac conduction atrioventricular in patients with conduction abnormalities preexisting, and may worsen bradycardia, heart block and congestive heart failure Other minor adverse effects of calcium channel antagonists include peripheral edema, vertigo, dizziness, headache, nausea and flushing, especially with nifedipine and nicardipine.

Many other agents are available for Treat essential hypertension. These agents include prazosin and terazocine, alpha 1 adrenergic receptor antagonists whose antihypertensive effects are due to arterial vasodilation resulting; clonidine, an alpha2 adrenergic agonist that acts centrally as well as peripherally in the alpha2 receptors adrenergic inhibitors, decreasing the sympathetic response. Others Centrally acting agents include methyldopa, guanabenz and guanfacine; reserpine, which acts by reducing the reserves of catecholamines; guanadrel, a peripheral adrenergic antagonist similar to guanetidine with a shorter duration of action; Y direct acting vasodilators such as hydralazine and minoxidil These agents, although effective, produce effects appreciable symptomatic side effects, including stimulation sympathetic reflex and fluid retention, orthostatic hypotension and impotence

Many antihypertensive agents activate compensatory vasotensive mechanisms, such as release increased renin, elevated aldosterone secretion and tone Increased sympathetic vasoconstrictor, which are designed to return blood pressure to pretreatment levels, and that they can lead to the retention of salts and water, edema and finally to tolerance to the antihypertensive actions of the agent. Further, due to the wide variety of side effects experienced with the present complement of antihypertensive drugs and problems experienced with them by special populations of hypertensive patients, including the elderly, blacks and patients with chronic obstructive pulmonary disease, diabetes or diseases peripheral vascular, there is a need for additional classes of drugs to treat hypertension.

Ischemia

Myocardial ischemia is the result of a imbalance of the contribution and the need for myocardial oxygen, and includes myocardial exertion and vasopastic dysfunction. The stress ischemia is generally attributed to the presence of Critical atherosclerotic stenosis involving the arteries large coronary arteries, resulting in a reduction in subendocardial flow. Vasospastic ischemia is associated with a focal variety spasm, whose onset is not associated with exercise or stress. Spasm is best defined as a sharp increase in vascular tone The mechanisms of vasospastic ischemia include: (i)  Increased vascular tone at the site of stenosis due to increased release of catecholamines; (ii) Obstruction transient intraluminal and (iii) Substance Release vasoactive formed by platelets at the location of endothelial lesions

The coronary circulation is unique, since perfuses the organ that generates the perfusion pressure for all the circulation. Thus, interventions that alter the state of the peripheral circulation and contractility will have an effect deep on the coronary circulation. The regulatory component of the coronary vasculature are the small coronary arterioles, which can greatly alter its internal diameter. Alteration of the internal radius is the result of the intrinsic contraction of the vascular smooth muscle (self-regulation) or compression extravascular due to ventricular contraction. The net effect of  therapies about the ischemic problem involves an interaction complex of opposing factors that determine the contribution and need for oxygen

Cardioprotection and prevention of ischemic injury

The development of new therapeutic agents able to limit the extent of myocardial injury, that is, the extent of myocardial infarction, after ischemia Acute myocardial is of great interest for cardiology modern

The advent of thrombolytic therapy (clot dissolution) over the past decade shows that the Early intervention during myocardial infarction can give as result in significant reduction of damage to myocardial tissue. Large clinical studies have since documented that the thrombolytic therapy decreases the risk of developing alterations of the heartbeat, and also maintains the ability of the heart To function as a pump. It has been shown that this conservation of normal cardiac function reduces long-term mortality after the heart attack

There has also been interest in the development of therapies capable of providing additional myocardial protection that could be co-administered with the therapy thrombolytic, or alone, since epidemiological studies retrospectives have shown that mortality during first years after the infarction seems to be related to the original infarct size.

In preclinical studies of infarction, carried out carried out in a variety of animal models, it has been shown that many types of pharmacological agents, such as blockers of calcium channels, prostacyclin analogues and agents capable of inhibit certain metabolic pathways, they are able to reduce the injury Ischemic in several animal species.

Recent studies have shown that the Myocardial exposure to brief periods of ischemia (interruption of blood flow to the heart), followed by reperfusion (restoration of blood flow) is capable of protect the heart from subsequent ischemic injury than from another form would derive from subsequent exposure to another period length of ischemia This phenomenon has been called myocardial preconditioning, and is believed to be attributable partially to the release of adenosine during the period of preconditioning

Other studies have shown that adenosine and adenosine agonists reduce the extent of tissue damage seen after interruption of blood flow to the heart in a variety of models of ischemic injury in several species (see, for example, Toombs, C . et al ., "Myocardial protective effects of adenosine. Infarct size reduction with pretreatment and continued receptor stimulation during ischemia.", Circulation 86 , 986-994 (1992); Thornton, J. et al ., "Intravenous pretreatment with A_ { 1} -selective adenosine analogs protects the heart against infarction. ", Circulation 85 , 659-665 (1992); and Downey, J.," Ischemic preconditioning - nature's own cardioprotective intervention. ", Trends Cardiovasc. Med. 2 (5 ), 170-176 (1992)).

The compounds of the present invention mimic the myocardial preconditioning, thereby improving the injury ischemic or producing a reduction in the size of the infarction of myocardium consequent to myocardial ischemia, and therefore they are useful as cardioprotective agents.

Antilipolysis

It is known that hyperlipidemia e Hypercholesterolemia are two of the main risk factors for atherosclerosis and coronary heart disease, the cause Main death and disability in Western countries. Although the etiology of atherosclerosis is multifactorial, the development of atherosclerosis and diseases that include coronary heart disease, peripheral vascular disease and disease cerebrovascular, which are derived from limited blood flow, are associated with alterations in serum cholesterol levels and lipids The etiology of hypercholesterolemia and hyperlipidemia is primarily genetic, although such factors may contribute as the dietary intake of saturated fats and cholesterol.

The antilipolytic activity of adenosine and adenosine analogues results from the activation of the A1 receptor subtype (Lohse, MJ, et al ., Recent Advances in Receptor Chemistry , Melchiorre, C. and Gianella, Eds, Elsevier Science Publishers BV, Amsterdam, 1988 , 107-121). Stimulation of this receptor subtype decreases the concentration of intracellular cyclic AMP in adipocytes. Cyclic AMP is a necessary cofactor for the enzyme lipoprotein lipase, which hydrolytically breaks down triglycerides to free fatty acids and glycerol in adipocytes (Egan, JJ, et al ., Proc. Natl. Acad. Sci . 1992 (89), 8357 -8541). Consequently, reducing the concentration of intracellular cyclic AMP in adipocytes reduces the activity of lipoprotein lipase and, therefore, the hydrolysis of triglycerides.

Blood pressure and plasma lipids elevated, which include triglycerides, are two factors of Accepted risks associated with mortality resulting from the cardiovascular disease

For the diabetic patient, in whom the probability of mortality from cardiovascular disease is substantially higher, the risk associated with these factors increases further (Bierman, EL, Arteriosclerosis and Thrombosis 1992 (12), 647-656). In addition, the data suggest that excessive lipolysis is characteristic of non-insulin-dependent diabetes and possibly contributes to insulin resistance and hyperglycemia (Swislocki, AL, Horm. Metab. Res . 1993 (25), 90-95).

The compounds of the present invention, such as antihypertensive and antilipolytic agents, are useful in the treatment and improvement of vascular risk factors and metabolic, and are of particular value and utility.

The present invention relates to a class of adenosine agonists and their usefulness in the treatment of hypertension, myocardial ischemia, as cardioprotective agents that improve ischemic injury or infarct size of myocardium resulting from myocardial ischemia, and as agents antilipolytics that reduce plasma lipid levels, the serum triglyceride levels and cholesterol levels plasma, and the methods and intermediates used in the preparation of such compounds.

2. Progress reported

Adenosine has a wide variety of physiological and pharmacological actions, which include an alteration appreciable cardiovascular and renal function. In animals and man, intravenous injection of adenosine nucleotide It causes hypotension.

The physiological and pharmacological actions of the adenosine are mediated through specific receptors located on cell surfaces. Two have been identified Adenosine receptor subtypes, designated as receptors A_ {1} and A_ {2}. The A 1 receptor inhibits the formation of cAMP inhibiting the activity of adenylate cyclase, while the stimulation of A2 receptors increases the activity of adenylate cyclase and intracellular cAMP. Each receiver seems mediate specific actions of adenosine in different tissues: for example, the vascular actions of adenosine appear to be mediated through stimulation of A2 receptors, what which is supported by the positive correlation between the generation of cAMP and vasorelaxation in vascular smooth muscle isolated treated with adenosine; while receptor stimulation A_ {1} cardiac reduces cAMP generation in the heart, which which contributes to dromotropic, inotropic and cardiac effects negative chronotropes. Consequently, unlike most of vasodilators, the administration of adenosine does not produce reflex tachycardia.

Adenosine also exerts an influence appreciable about renal function. The intrarenal infusion of adenosine causes a transient fall in renal blood flow and an increase in renal vascular resistance. With an infusion continued adenosine, renal blood flow returns to the Control levels and renal vascular resistance is reduced. The Initial renal vasoconstrictor responses to adenosine do not they are due to the direct vasoconstrictor actions of the nucleotide, but involve an interaction between adenosine and the system renin-angiotensin.

Adenosine is considered the physiological mediator Primary reactive hyperemia and bed self-regulation coronary in response to myocardial ischemia. It has been reported that The coronary endothelium has A2 adenosine receptors attached to adenylate cyclase, which are activated in parallel with the increments of coronary flow, and those cardiomyocyte receptors are predominantly of the A1 subtype of adenosine, and are associated with bradycardia. Consequently, adenosine offers a unique mechanism of ischemic therapy.

The cardiovascular responses to adenosine are Short-term due to rapid absorption and metabolism of the endogenous nucleotide. By contrast, adenosine analogues they are more resistant to metabolic degradation, and it has been reported that produce sustained alterations in blood pressure and heart rate.

Several powerful analogues have been synthesized metabolically stable adenosine, which demonstrate degrees selectivity variables for the two receptor subtypes. The adenosine agonists have generally shown a selectivity higher by the A1 receptors compared to the receptors A_ {2}. Cyclopentyladenosine (CPA) and R-Phenylisopropyl Adenosine (R-PIA) are standard adenosine agonists that show an appreciable selectivity for the A 1 receptor (ratio A 2 / A 1 = 780 and 106, respectively). By contrast, N-5'-ethyl-carboxamido adenosine (NECA) is a potent A2 receptor agonist (Ki-12 nM), but has an equal affinity for the A 1 receptor (Ki-6.3 nM; proportion A_ {2} / A_ {1} = 1.87). Until recently, CV-1808 he was the most selective A2 agonist available (A 2 / A 1 = 0.19), although the compound was 10 times less potent than NECA in its affinity for the A2 receptor. In progress Recent, new compounds have been described that are very potent and selective A 2 agonists (Ki = 3-8 nM for A 1; proportion A 2 / A 1 = 0.027-0.042).

It has been reported in the literature that various N6-aryl adenosines and N6-substituted heteroarylalkyl, and (2-amino and 2-hydroxy) substituted adenosines possess a varied pharmacological activity, which includes cardiac activity and circulatory See, for example, patent specification British 1,123,245, German disclosure 2,136,624, disclosure German 2,059,922, German disclosure 2,514,284, patent South African No. 67/7630, U.S. Pat. No. 4,501,735, publication EP No. 0139358 (which describes N6- [geminal diaryl alkyl substituted] adenosines), EP Publication No. 305,643 (which describes that heterocycle substituted adenosine derivatives in N6 exhibit cardiac vasodilator activity), disclosure German 2,131,938 (which describes aryl and heteroaryl derivatives alkyl hydrazinyl adenosine), German disclosure 2,151,013 (which describes aryl and heteroaryl substituted adenosines in N6), German disclosure 2,205,002 (which describes adenosines with N6 substituents comprising attached ring structures by single bond that bind N6 nitrogen to substituents that include thienyl) and South African patent No. 68/5477 (which describes 2-hydroxy adenosines substituted with N6-indolyl).

Pat. from the USA No. 4,954,504 and the publication EP No. 0267878 generically describe that ribose analogs carbocyclic adenosine, and its esters pharmaceutically acceptable, substituted in positions 2 and / or N6 by aril groups lower alkyl including thienyl, tetrahydropyranyl, tetrahydrothiopyranyl and heterocyclic lower alkyl derivatives saturated 5 or 6 benzofused bicyclic members exhibit agonist properties of adenosine receptor. Analogs of adenosine having thienyl type substituents are described in EP Publication No. 0277917 (which describes substituted adenosines in N6 with 2-heteroarylalkylamino, which include adenosine substituted with 2 - [(2- [thien-2-yl] ethyl) amino]), German disclosure 2,139,107 (which describes N6- [benzothienylmethyl] -adenosine), PCT document WO 85/04882 (which describes that substituted adenosine derivatives with heterocyclic alkyl in N6, which include N6- [2- (2-thienyl) ethyl] amino-9- (D-ribofuranosyl) -9H-purine, exhibit cardiovascular vasodilator activity and that the chiral substituents in N6 exhibit increased activity), the published application EP No. 0232813 (which describes that adenosines substituted with (thienyl 1-substituted) cyclopropylmethyl in N6 exhibit cardiovascular activity), US Pat. No. 4,683,223 (which describes that benzothiopyranyl substituted adenosines in N6 exhibit antihypertensive properties), PCT WO documents 88/03147 and WO 88/03148 (which describe that adenosines replaced with N6- [2-aryl-2-tien-2-yl)] ethyl exhibit antihypertensive properties), US Pat. nºs 4,636,493 and 4,600,707 (which describe that substituted adenosines with benzothienylethyl in N6 exhibit properties antihypertensive).

It is described that the amides of Adenosin-5'-carboxylic acid have utility as antihypertensive and antianginal agents in US Pat. 3,914,415, while US Pat. 4,738,954 describes that Aryl 5'-ethyl carboxamides and arylalkyl-substituted adenosine in N6 exhibit various cardiac and antihypertensive properties.

In EP publication No. 0.378.518 and the application R.U. 2,226,027 describes that the N 6 -alkyl-2'-O-alkyl Adenosines have antihypertensive activity. It is also reported than the N 6 -alkyl-2 ', 3'-di-O-alkyl Adenosines have utility as antihypertensive agents, patent from the USA 4,843,066.

It is reported that adenosine-5 '- (N-substituted) carboxamides and carboxylate esters and their N1-oxides are coronary vasodilators, Stein et al ., J. Med. Chem. 1980 , 23, 313-319 and J. Med Chem 19 (10), 1180 (1976). It is also reported that adenosine-5'-carboxamides and their N1-oxides are poisons of small animals in US Pat. 4,167,565.

The antilipolytic activity of adenosine is described in Dole, VP, J. Biol. Chem . 236 (12), 3125-3130 (1961). Inhibition of lipolysis by (R) -N6 phenylisopropyl adenosine is described in Westermann, E., et al ., Adipose Tissue. Regulation and Metabolic Functions , Jeanrenaud, B. and Hepp, D. Eds., George Thieme, Stuttgart, 47-54 (1970). It is described that the N6-mono- and bis-substituted adenosine analogs have antilipolytic, antihypercholesterolemic and antihyperlipemic activity in Pat. from the USA Nos. 3,787,391, 3,817,981, 3,838,147, 3,840,521, 3,835,035, 3,851,056, 3,880,829, 3,929,763, 3,929,764, 3,988,317 and 5,032,583.

It is believed that the reported toxicity, CNS properties and elevated heart rate associated with adenosine analogues have contributed to the difficulties that prevent the development of an antihypertensive / anti-ischemic agent of commercial adenosine analog. WO92 / 05177 describes a class of metabolically stable adenosine antagonists, and their derivatives, used in the treatment of myocardial ischemia. The The present invention relates to a class of adenosine agonists metabolically stable, and its derivatives, which possess properties unexpectedly desirable pharmacological agents, that is, they are agents antiischemic and antilipolytic agents that have a therapeutic profile only.

Summary of the invention

The compounds of the present invention are described by formula I

one

in the what:

K is N or N?

Q is CH2 or O;

T is two or R 3 O-CH 2;

X is a C1-C20 alkylene of linear or branched chain, or carbocyclic group C4-C8 1,2 or 1,3-bivalent, each of which is optionally substituted by at least one CH 3, CH 3 CH 2, Cl, F, CF 3 or CH 3 O;

Y is NR4, O or S;

a = 0 or 1;

Z is of formula 3

Z_ {1} is N, CR_ {5}, (CH) m -CR5 or (CH) m -N, with m 1 or 2;

Z 2 is N, NR 6, O or S, with n 0 or one;

R1, R2, R3, R4, R5 and R 6 are independently H, C1-C20 alkyl, phenyl unsubstituted or substituted with one or more substituents selected from C1-C20 alkyl, alkoxy C1-C20, amino, nitro, carboxyl, carbo alkoxy C1-C20, cyano, C1-C20 amino alkyl, halo, hydroxy, C1-C20 hydroxyalkyl, mercapto, C1-C20 alkyl mercapto, carbalquil C1-C20 and carbamoyl, or heterocyclyl 4 to 10 members in which one or more ring atoms are N, O or S, in the that said heterocyclyl ring is unsubstituted, or substituted with one or more substituents selected from alkoxy C1-C20, C1-C20 alkyl amino, phenyl, C1-C20 carbalkyl, carbamoyl, cyano, halo, hydroxy, mercapto, C1-C20 alkyl mercapto and nitro;

R_a and R_b are independently H, OH, C1-C20 alkyl, hydroxyalkyl C1-C20, C1-C20 alkyl mercapto, C1-C20 thioalkyl, C1-C20 alkoxy, C1-C20 alkyloxy C1-C20 alkyl, amino, C1-C20 alkylamino, carboxyl, acyl C1-C6, halogen carbamoyl, carbamoyl C1-C20 alkyl, unsubstituted or substituted phenyl with one or more substituents selected from alkyl C1-C20, C1-C20 alkoxy, amino, nitro, carboxyl, C1-C20 carboalkoxy, cyano, alkyl C1-C20 amino, halo, hydroxy, hydroxyalkyl C1-C20, mercapto, C1-C20 alkyl mercapto, C1-C20 carbalkyl and carbamoyl, or 4 to 10-membered heterocyclyl, in which one or more atoms of the ring are N, O or S, wherein said heterocyclyl ring is without replace or substituted with one or more substituents selected from C1-C20 alkoxy, C1-C20 amino alkyl, phenyl, C1-C20 carbalkyl, carbamoyl, cyano, halo, hydroxy, mercapto, C1-C20 alkyl mercapto and nitro; Y

R 'and R' 'are independently hydrogen, C1-C20 alkyl, C1-C20 phenylalkyl, carbamoyl, C1-C20 alkyl carbamoyl, dialkyl C1-C20 carbamoyl, C1-C6 acyl, C1-C20 alkyloxycarbonyl, phenylalkoxycarbonyl C1-C20, or phenyloxycarbonyl, wherein said ring phenyl is unsubstituted or substituted with one or more substituents selected from C1-C20 alkyl, alkoxy C1-C20, amino, nitro, carboxyl, carbalkyl C1-C20, cyano, C1-C20 alkyl amino, halo, hydroxy, C1-C20 hydroxyalkyl, mercapto, C1-C20 alkyl mercapto, carbalkyl C1-C20 and carbamoyl, or R 'and R' 'can form together

4 wherein R c is hydrogen or C1-C20 alkyl,

5 wherein R d and R e are independently hydrogen, C1-C20 alkyl, or together with the carbon atom to which they are attached can form a 1,1-cycloalkyl group;

provided that when X is alkylene C1-C20 linear chain and Q is oxygen, Z represents a heterocyclyl that includes at least two heteroatoms;

or its pharmaceutically acceptable salt, in the preparation of a medicament for use in the prevention of ischemic lesion

This invention also relates to compositions. pharmaceuticals to treat hyperlipidemia or hypercholesterolemia, which include an antilipolytic amount of formula I, and at methods and intermediates used in the preparation of such compounds.

Detailed description

As used before and throughout the detailed description of the invention, the following terms, to Unless stated otherwise, it is understood that they have following meanings:

"Acyl" means a group C-alkyl = O linear or branched. Acyl groups Preferred are lower alkanoyls having 1 to about 6 carbon atoms in the alkyl group.

"Alkyl" means a hydrocarbon group saturated aliphatic that can be linear or branched, and that has about 1 to about 20 carbon atoms in the chain. Branched means that a lower alkyl group, such as methyl, ethyl or propyl, is attached to an alkyl chain linear.

"Lower alkyl" means a group alkyl having 1 to about 6 carbons.

"Alkylene" means a chain of linear or branched bivalent hydrocarbon having 1 to Around 20 carbon atoms. Preferred alkylene groups they are the lower alkylene groups that have 1 to about 6 carbon atoms The most preferred alkylene groups are methylene, ethylene, ethylethylene, methylethylene and dimethylethylene.

"Cycloalkylene" means a group 1,2- or 1,3-bivalent carbocyclic which It has about 4 to about 8 carbon atoms. The groups Preferred cycloalkylene include 4,5-cis-  or trans-cyclohexenylene, 1,2-cyclohexanylene and 1,2-cyclopentylene.

"Optionally substituted" means that a Substituents or substituents given may be present or not.

"Alkyl amino" means an amino group substituted by one or two alkyl groups. Alkyl groups Preferred are lower alkyl amino groups.

"Alkyl carbamoyl" means a group carbamoyl substituted by one or two alkyl groups. They prefer lower alkyl carbamoyl groups.

"Alkyl mercapto" means an alkyl group replaced by a mercapto group. Alkyl groups are preferred Mercapto inferior.

"Alcoxi" means a group alkyl-oxy in which "alkyl" is as described previously. Lower alkoxy groups are preferred. Exemplary groups include methoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.

"Alkoxyalkyl" means an alkyl group, as previously described, substituted by an alkoxy group, as It was previously described.

"Aralkyl" means an alkyl group substituted by an aryl radical, in which "aryl" means a phenyl or phenyl substituted with one or more substituents that they can be alkyl, alkoxy, amino, nitro, carboxyl, carboalkoxy, cyano, alkyl amino, halo, hydroxy, hydroxyalkyl, mercapto, alkyl mercapto, carbalkyl or carbamoyl.

"Carbalkoxy" means a substituent carboxyl esterified with an alcohol of formula C_ {n} H_ {2n + 1} OH, in which n is from 1 to about 6.

"Halogen" (or "halo") means chlorine (chlorine), fluorine (fluoro), bromine (bromine) or iodine (iodine).

"Heterocyclyl" means a structure void from about 4 to about 10 members, in which one or more of the ring atoms is a non-carbon element, eg, N, O or S.

The representative heterocyclic fractions that they comprise the N6 substituent of the compounds of formula I They include the following:

6

Preferred heterocyclic groups include thienyl, thiazolyl and benzothiazolyl groups, substituted or not, in which substituents can be one or more group members alkoxy, alkylamino, aryl, carbalkoxy, carbamoyl, cyano, halo, hydroxy, mercapto, alkylmercapto or nitro.

"Hydroxyalkyl" means an alkyl group substituted by a hydroxyl group. Groups are preferred lower hydroxyalkyl. Preferred Exemplary Groups include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl.

"Prodrug" means a compound that may or may not be biologically active by itself but that may, by metabolic, solvolitic or other physiological means, Become a biologically active chemical entity.

"Cardioprotection" refers to the effect by which myocardium becomes less susceptible to ischemic injury and myocardial infarction resulting from ischemia myocardial

"Improvement of ischemic injury" means the prevention or reduction of ischemic myocardial injury consequent to myocardial ischemia.

"Improvement of myocardial infarction size" means the reduction of myocardial infarction size, or the prevention of myocardial infarction, consequent to ischemia myocardial

The compounds of formula I include preferably a chiral center (asymmetric). For example, the Preferred compounds having such an asymmetric center comprise compounds, e.g., in which X is isopropylene, and has a R or S configuration, with R being the most preferred. The invention includes the individual stereoisomers and mixtures thereof. Isomers individual are prepared or isolated by well methods known in the art, or by methods described herein.

The compounds of the invention can be used as a free base, in the form of acid addition salts or as hydrates. All these forms are within the scope of the invention. Acid addition salts are simply a more convenient way of use. In practice, the use of the salt form inherently amounts to the use of the basic form. Acids that can be used to prepare acid addition salts preferably include those that produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are not toxic to the recipient in pharmaceutical doses of the salts, so that the beneficial anti-ischemic and antilipolytic effects produced by the free base are not vitiated by the side effects attributable to the anions. Although pharmaceutically acceptable salts of the compounds of the invention are preferred, all acid addition salts are useful as sources of the free base form, even if the particular salt is desired, per se , only as an intermediate as, for example, when the salt is formed solely for the purpose of purification and identification, or when it is used as an intermediate to prepare a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, fumaric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid and the like. The corresponding acid addition salts comprise the following: hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, fumarate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfonate and quinate, respectively.

The acid addition salts of the compounds of the invention are conveniently prepared by dissolving the base free in aqueous or aqueous-alcoholic solution or other suitable solvents containing the appropriate acid, and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of dissolution

Within the scope of formula I are including classes of compounds that can be characterized generally as adenosines substituted with heterocycles in N6; carbocyclic adenosines substituted with heterocycles in N6 (or, alternatively, dihydroxy [substituted with heterocycles in N6-9-adenyl] cyclopentanes) and their N-oxides; Y N'-1-deazaaristeromycins substituted with heterocycle in N6 (or, alternatively, substituted dihydroxy [[4,5-b] imidazopyridyl with heterocycle in N7] -cyclopentanes). They are also within the scope of formula I derivatives 5'-alkylcarboxamide of adenosines, carbocyclic adenosines and 1-deazaaristeromycins, derivatives of compounds of the above classes in which they are substituted one or both of the hydroxyl groups in 2 or 3 of the ring of cyclopentane or, in the case of the classes of compounds that contain  the ribose fraction, hydroxyl groups in 2 'or 3' of the ring of ribose Such derivatives may comprise the chemical entity biologically active useful as an antilipolytic agent, or they can act as prodrugs for such compounds biologically assets that are formed from them in conditions physiological

The representative compounds of the invention include: N6- [trans-2- (thiophen-2-yl) cyclohex-4-en-1-yl] adenosine; N6- [trans-2- (thiophen-3-yl) -cyclohex-4-en-1-yl] adenosine; N6- [trans-2- (thiophen-2-yl) cyclohex-4-en-1-yl] adenosin-5'-N-ethyl carboxamide; N6- [2- (2'-aminobenzothiazolyl) ethyl] adenosine; N6- [2- (2'-thiobenzothiazolyl) ethyl] adenosine; N6- [2- (6'-ethoxy-2'-thiobenzothiazolyl) ethyl] adenosine; N6- [2- (2'-aminobenzothiazolyl) ethyl] adenosine-5'-N-ethyl carboxamide; N6- [2- (2'-aminothiazolyl) ethyl] adenosine carbocyclic-5'-N-ethyl  carboxamide; N6- [2- (4'-methylthiazol-5'-yl) ethyl] adenosine;  N6- [2- (2'-thiazolyl) ethyl] adenosine; N6 - [(R) -1- (5'-chlorothien-2'-yl) -2-propyl] adenosine-5'-N-ethyl carboxamide; N6- [2- (2'-methyl-4'-thiazolyl) -ethyl] adenosine; N6 - [(R) -1-methyl-2- (2'-benzo [b] thiophenyl) ethyl] adenosine; N6- [2- (4 '' - methyl-5 '' - thiazolyl) ethyl] adenosine carbocyclic-5'-N-ethyl carboxamide; N6- [2- (2 '' - thiazolyl) ethyl] adenosine carbocyclic-5'-N-ethyl carboxamide; N6- [2- (4'-phenyl-2'-thiazolyl) ethyl] adenosine; N6 - [(R) -1- (5 '' - chloro-2 '' - thienyl) prop-2-yl] adenosine carbocyclic-5'-N-ethyl  carboxamide; (-) - N6- (thiophen-2 '' - il) ethan-2-yl] adenosine carbocyclic-5'-N-ethyl  carboxamide; N6- [1- (thiophen-3-yl) ethan-2-yl] adenosine carbocyclic-5'-N-ethyl  carboxamide; N6 - [(R) -1 - ((thiophen-2-yl) prop-2-yl)] adenosine carbocyclic-5'-N-ethyl carboxamide; N6- [1- (thiophen-2-yl) ethan-2-yl] -N'-1-deazaaristeromycin-5'-N-ethyl  carboxamide; N6 - [(R) -1 - ((thiazo-2-yl) -prop-2-yl)] adenosin-5'-N-ethyl carboxamide; N6- [1- (thiophen-2-yl) -2-methylpropyl] adenosin-5'-N-ethyl carboxamide; N6 - [(R) -1- (5'-chlorothien-2-yl) -2-butyl] adenosine carbocyclic-5'-N-ethylcarboxamide; N6- [2- (4'-methyl-2-thiazolyl) ethyl] adenosine; N6- [4'-phenyl-2'-thiazolyl) methyl] adenosine; (-) - [2S- [2α, 3α-dimethylmethylenedioxy-4-β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino] -9-adenyl] cyclopentan] -1-? N-ethylcarboxamide; (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methyl ethyl] amino-9-adenyl] cyclopentan-1? -N-ethylcarboxamide; (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan-1β-N-ethylcarboxamide-N1-oxide; [1S- [1α, 2β, 3β, 4α (S *)]] - 4- [7 - [[2- (5-chloro-2-thienyl) -1-methylethyl] amino ] -3H-imidazo [4,5-b] pyridin-3-yl] -N-ethyl-2, 3-dihydroxycyclopentan-carboxamide; [1S-1α, 2β, 3β, 4α]] -4- [7 - [[2- (3-chloro-2-thienyl) -1-ethylethyl] amino] -3H-imidazo [4,5-b] pyridin-3-yl] -N-ethyl-2, 3-dihydroxycyclopentan-carboxamide; [1S-1α, 2β, 3β, 4α]] -4- [7 - [[2- (2-thienyl) -1-isopropylethyl] amino] -3H-imidazo [4,5 -b] pyridin-3-yl] -N-ethyl-2,3-dihydroxycyclopentan-carboxamide; [1S-1α, 2β, 3β, 4α (S *)]] - 4- [7 - [[2- (3-chloro-2-thienyl) -1-ethylethyl] amino] -3H-imidazo [4,5-b] pyridin-3-yl] -N-ethyl-2,3-dihydroxycyclopentan-carboxamide; [1S-1α, 2β, 3β, 4α (S *)]] - 4- [7 - [[2- (2-thienyl) -1-methylethyl] amino] -3H-imidazo [4,5-b] pyridin-3-yl] -N-ethyl-2, 3-dihydroxycyclopentan-carboxamide; [1S-1α, 2β, 3β, 4α]] -4- [7 - [[2- (5-chloro-2-thienyl) -1-ethylethyl)] amino] -3H- imidazo [4,5-b] pyridin-3-yl] -N-ethyl-2,3-dihydroxycyclopentan-carboxamide; (2S) -2α, 3α-bis-methoxycarbonyloxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan-1β-N-ethylcarboxamide; (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan-1β-N-ethylcarboxamide ethoxymethylene acetal; (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan- 1β-N-ethylcarboxamide-2, 3-carbonate; (2S) -2α, 3α-bis-methylcarbamoyloxy-4β - [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan-1β-N-ethylcarboxamide; (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methyl ethyl] amino-9-adenyl] cyclopentan-1β-N-ethylcarboxamide-2,3-thiocarbonate; N 6 - [2- (3-Chloro-2-thienyl) - (1 R) -1-methylethyl] -2'-O-methyladenosine; N 6 - [2- (5-chloro-2-thienyl) - (1 R) -1-methylethyl] -2'-O-methyladenosine; Y N 6 - [trans-5- (2-thienyl) cyclohex-1-en-4-yl] -2'-O-methyladenosine.

A preferred class of compounds of the invention It is described by formula I, in which R 'and R' 'are H.

Another preferred class of compounds of the invention are derivatives 5'-N-alkylcarboxamide of carbocyclic adenosines substituted with heterocycles in N6, in in other words, the compounds of formula I, in which K is N, Q is CH 2 and T is R 1 R 2 N-C = O, or its salts pharmaceutically acceptable.

The most preferred class of compounds of the invention comprises the compounds of formula I characterized by the presence of an alpha chiral center in the N6 atom of purine or 1-deazapurine ring, while an embodiment Special of this class includes compounds characterized by a chiral ethyl group attached to the alpha carbon atom with respect to the nitrogen N6. A particularly preferred class of compounds is characterized by an N6- [1-alkyl substituent group lower-2- (3-halotien-2-yl) ethyl].

The most preferred embodiments of the invention they comprise the compounds (-) - [2S- [2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) -1- (R) -methylethyl] -amino] -9-adenyl] cyclopentan] -1β-ethylcarboxamide ,  (-) - [2S- [2α, 3α-dihydroxy-4β- [N6- [1- (R) -ethyl-2- (3-chloro-2-thienyl) ethyl] amino] -9-adenyl] cyclopentan-1? -ethylcarboxamide, [1S-1α, 2β, 3β, 4α (S *)]] - 4- [7 - [[2- (5-chloro-2-thienyl) -1-methylethyl] amino] -3H-imidazo [4,5-b] pyridin-3-yl] -N-ethyl-2, 3-dihydroxycyclopentancarboxamide, [1S- [1α, 2β, 3β, 4α (S *)]] - 4- [7 - [[2- (3-chloro-2-thienyl) -1-ethylethyl] amino ] -3H-imidazo [4,5-b] pyridin-3-yl] -N-ethyl-2,3-dihydroxycyclopentancarboxamide, and its pharmaceutically acceptable salts.

The compounds of this invention can be prepare by known methods or according to the sequences of reaction described below. The starting materials used in the preparation of the compounds of the invention known or are commercially available, or can be prepared by known methods or by specific reaction schemes described here.

The compounds of formula I, in which K is N, Q is O and T is R 3 O-CH 2, can be prepared reacting 6-chloropurine riboside commercially available with various heterocyclic amines, such as It is exemplified below.

The compounds of formula I, in which K is N, Q is O and T is R 1 R 2 N-C = O, they are prepared from similar form starting from the product of reaction scheme A. In this reaction, 6-chloropurine riboside, with the 2 'and 3' hydroxyl groups of the protected ribose ring are treated with an oxidant, for example a Jones reagent, and the acid produced is treated with dicyclohexylcarbodiimide (DCC) or BOP-Cl in the presence of a selected amine, for produce the 5'-alkylcarboxamide derivative.

Reaction scheme TO

7

Suitable starting materials for the compounds of formula I in which K is N, Q is CH 2 and T is R 1 R 2 NC = O, can be prepared as described in Chen et al . , Tetrahedron Letters 30: 5543-46 (1989). Alternatively, reaction scheme B can be used to prepare such starting materials. Upon carrying out reaction scheme B, the 2,3-dihydroxycyclopentylamine 4-ethylcarboxamide derivative, prepared as described by Chen et al ., Is reacted with 3-amino-2,4-dichloropyrimidine. The product of this initial reaction is then heated with aldehydlamine acetate, for example, formamidine acetate in dioxane and methoxyethanol, for a time sufficient to effect the closure of the ring (from about 30 min to about 4 hours), thereby giving a product that can be conveniently reacted with various heterocyclic amines in the manner described below, to give the compounds of the invention. The order of the reaction is not critical. For example, the intermediate formed in reaction scheme B could be reacted with a heterocyclic amine, followed by ring closure to give the desired final product.

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Reaction scheme B

8

Various amines can be prepared heterocyclics, useful for forming the compounds of this invention, by one or more of the reactions shown in the C-J reaction schemes and preparative examples B to G, and 50 to 74, later (Het = heterocyclic group; Halo = halogen; R = eg H or lower alkyl; R_ {a} and Y are as described above).

Reaction scheme C

9

Reaction scheme D

10

Reaction scheme AND

eleven

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Reaction scheme F

12

Reaction scheme G

13

Reaction scheme H

14

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Reaction scheme I

fifteen

The reaction sequence of scheme I above It is described in US Pat. No. 4,321,398, with the information relevant incorporated here for reference.

Example B Preparation of 1- (thiophen-3-yl) ethylamine

3-thiophenecarboxaldehyde (1 mmol), nitromethane (1.5 mmol) and beta-alanine (0.1 mmol) in butanol for 6 hours to give 3-nitrovinylene thiophene, which Reduces with lithium aluminum hydride (2.5 mmol) to produce the Desired amine

3-substituted thienyl alkylamines are prepared replacing thiophenes substituted in 3, such as 3-chlorothiophene, for the starting materials of thiophene of Example B above.

Example C Preparation of trans-2- (thiophen-2-yl) cyclohex-4-enylamine

A mixture of 1,3-butadiene (5 ml) and 2-nitrovinylentiophene (7 g) in toluene at 140 ° C overnight in a sealed tube. Nitrocyclohexene resulting is hydrogenated (~ 2.46 kg / cm 2 of H 2) (5% Pd / C MeOH) and is treated with lithium aluminum hydride (2.5 g). I know get the trans-2- (thiophene-2-yl) -cyclohexylamine racemic with a standard procedure.

Example D General preparation of thiazole substituted amines in 2

Benzoyl chloride is reacted and aminopropionitrile to give N-benzoyl-aminopropionitrile, which is reacts with hydrogen sulfide in ammonia to produce thioamide, which is reacted with a α-halo ketone appropriate to produce the desired thiazole. The 5N hydrochloric acid treatment eliminates the benzoyl protecting group to give the desired amine product.

Example E General preparation of thiazolyl substituted amines in 4

A preferred synthesis of 2- (2'-methyl-4'-thiazolyl) ethylamine is to react thioacetamide with ethyl monobromoacetoacetate to give a thiazole ester, which is preferably reduced with sodium borohydride to produce the alcohol that becomes the amine. A preferred method for the amine comprises the treatment. with (1) diethylazodicarboxylate, triphenylphosphine and phthalimide and (2) hydrazine hydrate

The preparation of thiazole substituted amines in 4 it can also be carried out using the reaction scheme above, reacting a substituted thioamide and ethylmonobromoacetoacetate. Thiazolyl ester conversion resulting to the amide is carried out with aqueous ammonia, and the amine is shape by reduction with borane. A preparation is described copy of 2- (1,1-dimethyl-1'-thiophenyl) ethylamine in US Pat. No. 4,321,398.

Diastereoisomeric mixtures of the compounds or intermediates obtained in the reaction schemes Above A-I can be separated into enantiomers unique or optically active racemic by methods known in The technique; for example, by chromatography, distillation fractional or fractional crystallization of salts of d- or l- (tartrate, dibenzoyltartrate, mandelate or camphor sulfulfonate).

Example F Preparation of (+) and (-) trans-2- (thiophen-2-yl) cyclohex-4-enylamine

(S) - (+) - Mandelic acid (0.55 eq) is added to an isopropanol solution of the racemic amine (3.4 g) prepared in Example C. The precipitate is recrystallized from isopropanol to provide 1 , 78 g of salt
([α] D TA = + 4.13 (c = 1.3, MeOH)). The amines are isolated by extracting the neutralized salts (NaHCO 3 sat.) With CH 2 Cl 2, drying (Na 2 SO 4) and concentrating to provide partially resolved free amines.

Approximately 1 g of the levorotatory amine ([α] D TA = -25.8 (c = 1.54, MeOH)) is treated with 2 g of l - (-) - dibenzoyl tartaric acid in methanol, and the resulting salt is processed to provide 0.64 g of the levorotatory amine
([α] D TA = -28.8 (c = 1.65, MeOH)). High-field NMR analysis of the MPTA amide of the levorotatory amine revealed> 96% enantiomeric excess.

Approximately 1.6 g of the mixture is treated. dextrorotatory amine enriched with 3.2 g of acid d - (+) - dibenzoyl tartaric in methanol. Behind the processing, 0.87 g of the dextrorotatory amine is obtained ([α] D TA = + 25.8 (c = 1.67, MeOH)).

Adenosines substituted with heterocycles in N6 and the carbocyclic adenosines of the invention can be formed by reacting 6-chloropurine riboside or products of reaction schemes A or B with various amines heterocyclic, according to the synthetic route shown later in the reaction scheme J, in which K, P, Q and T are as defined previously.

Reaction scheme J

16

The N'-alkyl-deazaaristeromycins N6-substituted heterocycles of the invention can be prepare as shown in reaction scheme K.

Reaction scheme K

17

The compounds of the present invention that they can act as prodrugs include the compounds in which hydroxyl groups in ribose or cyclopentane ring are replace with groups R 'and R' ', as defined above for Formula I. These can be prepared by known methods, and are exemplified by the preparations shown in the scheme  of reaction L, later.

Reaction scheme L

18

Treatment of dihydroxy compounds with a chloroformate ester in the presence of an organic base, by example triethylamine, will give bis-carbonate correspondent. The alkoxymethylene acetal can be prepared by treatment with the corresponding orthoester in the presence of a catalytic amount of p-toluenesulfonic acid. The carbonate is available by treatment with 1,1'-carbonyldiimidazole, and thiocarbonate by Thiocarbonyldiimidazole treatment. The alkyl derivatives and dialkylcarbamoyl can be prepared by treatment with the alkyl isocyanate or dialkyl carbamoyl chloride corresponding in the presence of an organic base, respectively.

The compounds of the present invention in the that K is N →, that is, the N-oxides, can be prepare by oxidation of adenosine or adenosine corresponding carbocyclic by known methods, for example  by treatment with hydrogen peroxide in acid acetic.

Derivatives 2'-O-alkyl can be prepared by known methods, for example by reaction of the appropriate heterocyclic amine with 6-chloro-9- (2'-O-methyl-? -D-ribofuranosyl) -9H-purine.

The functional groups of the compounds of heading and intermediates used to prepare the compounds of the invention can be protected by common protecting groups known in the art. Conventional protecting groups for amino and hydroxyl functional groups are described, by example, in T.W. Greene, "Protective Groups in Organic Synthesis ", Wiley, New York (1984).

Hydroxyl groups can be protected as esters, such as acyl derivatives, or in the form of ethers. The hydroxyl groups in adjacent carbon atoms can be protected advantageously in the form of ketals or acetals. In practice, adjacent 2 'and 3' hydroxyl groups of the starting compounds in reaction schemes A and B are conveniently protected by forming  2 ', 3' isopropylidene derivatives. Free hydroxyls can be restore by acid hydrolysis, for example, or others solvolysis or hydrogenolysis reactions commonly used in organic chemistry

After synthesis, the compounds of the invention are typically purified by liquid chromatography to medium pressure (MPLC), in a Chromatotron, layer chromatography fine radially accelerated, sudden desorption chromatography or column chromatography through a silica gel matrix or Florsil, followed by crystallization. For the compounds of formula I where K is N, Q is O and T is R 3 O-CH 2, Typical solvent systems include chloroform: methanol, ethyl acetate: hexane and methylene chloride: methanol. Eluted can be crystallized from methanol, ethanol, acetate ethyl, hexane or chloroform.

For compounds of formula I, in which K is N, Q is O and T is R 1 R 2 N-C = O, the systems Typical solvents include chloroform: methanol. The eluted ones they can crystallize from 50-100% ethanol (aqueous).

For compounds of formula I, in which Q is CH 2, K is N or CH and T is R 1 R 2 N-C = O, Typical solvent systems include chloride methylene: methanol Eluates can be crystallized from ethyl acetate with or without methanol, ethanol or hexane.

Compounds that require neutralization are they can neutralize with a weak base such as sodium bicarbonate, followed by washing with methylene chloride and brine. The products which are purified in the form of oils are sometimes crushed with hexane / ethanol before final crystallization.

A further aspect of the present invention relates to an improved method for preparing a 2-amino-1- (heteroar-2- or 3-yl) ethane substituted 2 optically pure derivative. 2- (heteroaryl) ethylamines and their alkyl and phenyl derivatives have been prepared by a variety of means, including the reduction of 2-?-Nitrovinylheteroaryl compounds prepared from heteroarylformaldehydes (see, e.g., W. Foye and S. Tovivich, J. Pharm. Scien. 68 (5), 591 (1979), S. Conde, et al ., J. Med. Chem. 21 (9), 978 (1978), M. Dressler and M. Joullie, J. Het. Chem. 7 1257 (1970)); reduction of cyanomethylheteroaryl compounds (see, e.g., B. Crowe and F. Nord, J. Org. Chem. 15 , 81 (1950), J. McFarland and H. Howes, J. Med. Chem. 12 , 1079 (1969)); Hoffman degradation reaction of 2- (2-thienyl) propyl amide (see, eg, G. Barger and A. Easson, J. Chem. Soc. 1938 , 2100); and amination of 2- (2-thienyl) ethylparatoluenesulfonates, pat. from the USA No. 4,128,561.

The present method comprises reacting a ethylene oxide derivative substituted in 2 with a 2- or 3-yl anion of a heteroaryl compound, and convert,  by stereospecific means, the hydroxyl group formed in said reaction in an amino group. The method of the present invention is shown in reaction scheme M, below.

Reaction scheme M

19

In which Sub represents a substituent group of said chiral ethylene oxide and Het represents a group heterocyclic

An advantage of the method of the present invention on the methods of preparing derivatives of 2-amino-1- (heteroar-2-  or 3-yl) ethane substituted in 2 known in the art is the preparation directly from a derivative substantially pure optically, compared to the preparation of a racemic mixture that must be resolved later by others methods to produce optically pure isomers.

A preferred class of the method of the present invention is that in which the heteroar-2- group  or 3-yl is a thien-2-  or 3-yl substituted or not, or a group benzothiophene 2- or 3-yl replaced or not.

A more preferred class of the method of the present invention is that in which said anion is formed by react a thiophene or substituted benzothiophene or not, which has a hydrogen substituent in position 2 or 3, with a base organometallic in an aprotic organic solvent.

Another more preferred class of the method of The present invention is one in which said ethylene oxide substituted in chiral 2 is replaced in position 2 by a group selected from the group consisting of alkyl, aryl, trihalomethyl and benzyloxy.

A more preferred class of the method of the present invention is one in which said organometallic base is a alkyl lithium diisopropylamide, said organic solvent aprotic is tetrahydrofuran, ether, hexane or a mixture of those solvents, and said chiral 2 substituted ethylene oxide is a 2-alkyl ethylene oxide derivative.

Means for stereospecifically converting a hydroxy group into an amino group are well known in the art (see, eg, Mitsunobu, Synthesis 1981 (1), 1).

It should be apparent that derivative (R) or (S) -2-substituted-2-hydroxy-1-heteroaryletane can be formed directly as described above, by using the oxide derivative of (S) or (R) - Corresponding 2-substituted ethylene as a starting material or, if desired or necessary, a resulting (R) or (S) -2-substituted-2-hydroxy-1-heteroaryletane could be converted into derivative (S) or ( R) -2-Substituted-2-hydroxy-1-heteroaryletane corresponding, respectively, by means well known in the art, to reverse the configuration in the hydroxy group (see, eg, Mitsunobu, Synthesis 1981 (1), one).

A specific embodiment of the method of The present invention is one in which: (a) a thiophene or benzothiophene substituted or not, which has a hydrogen substituent in position 2 or 3, it is treated with butyllithium in a mixture of tetrahydrofuran and hexanes at reduced temperature, for example around -30 ° C, long enough to forming the anion of said thiophene or benzothiophene; (b) then it add an oxide of (S) or (R) 2-alkyl ethylene and the mixture is kept at a higher temperature, for example around 0 ° C, for a time sufficient to form derivative (R) or (S) 2-alkyl-2-hydroxy-1-thienyl or corresponding benzothiophenyl ethane; and (c) then it becomes, by stereospecific means, the hydroxy group of said derivative of ethane in an amino group.

The method of the present invention is illustrated and it is further explained by examples 50 to 74, more ahead.

Examples 1-3 describe the preparation of the precursor compounds used in the preparation of the compounds of the present invention, which are described more ahead.

Example 1  Preparation of 6-chloro-2 ', 3'-dimethyl-methylenedioxy-N-5'-ethyl carboxamido adenosine

Stage one

2 ', 3'-dimethylmethylene derivative of 6-Chloropurine Riboside

6-Chloropurine riboside is stirred (31.5 g), triethylortoformate (73 ml) and TsOH (19.8 g) in 600 ml of acetone for 2 hours at RT. The reaction mixture is concentrated at vacuum, combine with ethyl acetate and wash with solution saturated with NaHCO 3 and brine, dried (Na 2 SO 4) and dried concentrate to produce the derivative 2 ', 3'-dimethylmethylene of 6-Chloropurine Riboside Solid White.

Stage two

Acid 6-chloro-2 ', 3'-dimethylmethylenedioxy adenosine-5'-carboxylic

The product of Stage 1 (10 g) is subjected to Jones oxidation, the ethyl acetate acid is extracted with 2.5% NaOH solution, and the aqueous portion is washed with ethyl acetate and acidified with concentrated HCl, and extracted with ethyl acetate. The organic layer is washed with H2O and brine, dried (Na2SO4), filtered and concentrated to vacuum to dryness, producing acid Desired 5'-carboxylic.

Stage 3

6-Chloro-2 ', 3'-dimethylmethylenedioxy-N-5'-ethyl carboxamido adenosine

The product of Stage 2 (5.7 g) is stirred with BOP-Cl (chloride bis- (2-oxo-3-oxazoladinyl) phosphine) (4.26 g) and triethylamine (2.33 ml) in 100 ml of chloride of methylene for 20 min at RT. Ethylamine (3.46 g) is added with stirring to the solution, which is stirred for 2 hours at RT. The organic portion is washed with dilute HCl solution, NaOH diluted, H2O, brine and dried (Na2SO4), to provide the final product in foam form.

Example 2 Preparation of (+) - 2S- [2α, 3α-dimethylmethylenedioxy] -4β- [6-chloro-9-adenyl] cyclopentan-1-β-N-ethyl carboxamide

Stage one

5,6-dimethylenedioxy-2-azabicyclo [2,2,1] heptan-3-one

It dissolves 5,6-dihydroxy-2-azabicyclo [2,2,1] heptan-3-one (23.5 g) (Aldrich), or prepared according to the Cermak procedure and Vince, Nucleic Acid Chemistry, Improved and New Synthetic Procedures, Methods and Techniques, Part Three, page 26 (J. Wiley 1986), in acetone (150 ml) containing 2,2-dimethoxypropane (185 ml) and acid p-toluenesulfonic (5.25 g), and the mixture is refluxed for 10 min, cool, treat with NaHCO3 (9.3 g) and Concentrate in vacuo. The residue is dissolved in CH2Cl2, it is wash with brine, dry with MgSO4 and the solvent is evaporated to produce an oil The oil is chromatographed with SiO2 (4: 1, ethyl acetate: hexane) to give 17.0 g (63%) of a brownish white solid (mp 153-154 ° C).

Stage two

(+) - 4β-amino-2α, 3α-dimethylenedioxycyclopentan-1β-N-ethyl carboxamide

(A) It is 5,6-dimethylenedioxy-2-azabicyclo [2,2,1] heptan-3-one (5 g), prepared in Step 1, with ethylamine (15 ml) at 140 ° C for about 7 hours. The resulting product is purified by sudden desorption chromatography (CH 2 Cl 2 / CH 3 OH / N, N-dimethyl ethylamine, (90/7/3)) to produce (±) 4β-amino-2α, 3α-dimethylenedioxy cyclopentan-1? -ethylcarboxamide (5.8 g).

(B) The treatment of racemic amine (13.1 g), prepared as described in part A, with acid D-dibenzoyltartaric (21.6 g) gives 15.1 g of a salt enantiomerically pure, [α] D TA = +70.1 (C. 1.77, CH 3 OH). The salt is dissolved in 10% aqueous NaOH, and the phase Aqueous is extracted with ethyl acetate. Organic layers combined they are washed with brine, dried with MgSO4 and the Solvent is removed to give the optically pure compound. [α] D TA = +31.4 [C. 1.40, MeOH].

Stage 3

4-? - (3-amino-4-chloro-2-pyrimidinylamino) -2,3-dimethylene-dioxycyclopentan-1? -N-ethyl-carboxamide

Condensation of (+) - 4β-amino-2α, 3α-dimethylenedioxycyclopentan-1β-N-ethyl carboxamide (2.10 g), prepared in Stage 2, part B, with 3-amino-2,4-dichloropyridine (1.5 g) in n-butanol (70 ml) containing triethylamine (3 ml) for about 14 hours at reflux, followed solvent removal in vacuo, gives an oil that Dissolve in ethyl acetate and wash with aqueous NaHCO3. The organic extract is dried with Na2SO4 and concentrated to vacuum to produce the optically pure compound. [α] D TA = +15.8 (C. 41.48, CH 3 OH).

Stage 4

(+) - 4β- (3-amino-4-chloro-2-pyrimidinylamino) -2α, 3α-dimethylene dioxycyclopentane (2.10 g), formamidine acetate (1.85 g) in methoxyethanol (2 ml) and Dioxane (80 ml) is stirred at 70 ° C for about 3 hours. The mixture is cooled to room temperature and the solvent is removed under vacuum The residue is dissolved in ethyl acetate, which is washed With aqueous NaHCO3 and brine, the organic extract is dried with Na2SO4, is concentrated in vacuo and purified by sudden desorption column chromatography (chloride methylene / methanol 95: 5) to produce ( +) - [2α, 3α-dimethylmethylenedioxy] -4β- [6-chloro-9-adenyl] cyclopentan-1-β-N-ethyl pure carboxamide (1.45 g).

Alternatively, derivatives can be prepared 2α, 3α-diprotected dioxy-4β-6-substituted-9-adenyl-cyclopentan-1β-N-ethyl carboxamide by the reaction scheme exemplified in the Example 3

Example 3 Preparation of 2S- [2α, 3α-cyclohexylidenedioxy] -4β- [N6- (2-tenertan-2-yl) -9-adenyl] cyclopentan-1β-N-ethyl carboxamide

Stage one

4β-ethylene-2α, 3α- [cyclohexylidenedioxy] cyclopentanone

(-) - 2α, 3α- [cyclohexylidenedioxy] -4-cyclopentenone (2.95 g), prepared following the procedure of Borchardt et al . J. Org. Chem. 1987, 52, 5457, is added as a solution in THF (5 ml) to a mixture of vinyl magnesium bromide (15.2 mmol) and CuI (15.2 mmol) in THF (100 ml). This mixture is maintained at -78 ° C in an inert atmosphere for about 2 hours, heated to 0 ° C and stopped with saturated aqueous NH4Cl. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give a yellow oil, which is purified by flash chromatography (methylene chloride, 100%), to provide 2.9 g of the desired compound in the form of oil.

Stage two

4β-ethylene-1-β-hydroxy-2α, 3α- [cyclohexylidenedioxy] cyclopentane

3.95 ml of a 1M solution of hydride are added from diisobutylaluminum in tetrahydrofuran to a THF solution (75 ml) and the ketone prepared in Stage 1 (0.73 g), which is cooled at -78 ° C. The mixture is heated to -40 ° C for about 2.5 hours, it is treated with 2N NaOH (5 ml), heat to room temperature and stir for about 1.5 hours. The aqueous phase is extracted with diethyl ether, and the phases The combined organics are washed with brine, dried with MgSO4 and concentrate in vacuo to a yellow oil, which purify by flash column chromatography (methylene chloride / methanol, 95: 5), to produce 0.65 g of pure product in the form of viscous oil.

Stage 3

4β-ethylene-1β-trifuoromethanesulfonyl-2,3- [cyclohexylidenedioxy] cyclopentane

A solution of 4β-ethylene-1β-hydroxy-2α, 3α- [cyclohexylidenedioxy] cyclopentane (0.65 g) in methylene chloride (5 ml) and pyridine (0.24 ml) to a solution stirred of trifluoromethylsulfonic anhydride (0.49 ml) in chloride of methylene (25 ml) at 0 ° C in argon. After about 20 min, it add brine to the reaction mixture, the organic phase is dried in Na 2 SO 4 and the solvent is removed in vacuo to produce the desired product in the form of orange oil, which is used without additional purification

Stage 4

1β-ethylene- [2α, 3α-cyclohexylidenedioxy] -4-β- [N6- (2-thienylethane-2-yl) 9-adenyl] cyclopentane

A solution of N6-thiophenylethyl purine (2.13 g), NaH (dispersion 50% oily, 0.35 g) and 18-crown-6 (0.15 g) in DMF (60 ml) to a solution of 4β-ethylene-1β-trifuoromethylsulfonyl-2α, 3α- [cyclohexylidenedioxy] cyclopentane, prepared in the Stage 4, in DMF (2 ml) at 0 ° C. The mixture is stirred at 0 ° C for around 8 hours, stop with saturated NH4Cl, remove the solvent in vacuo and the residue is combined with ethyl acetate (100 ml) and brine. The organic layer is dried with MgSO4 and concentrated in vacuo, and the crude product is purified by flash chromatography (methylene chloride / methanol (99: 1)) to produce 0.85 g of the pure product.

Stage 5

2S [2α, 3α-cyclohexylidenedioxy] -4β- [N6- (2-thienylethane-2-yl) -9-adenyl] cyclopentan-1-β-N-ethyl carboxamide

A solution of 1β-ethylene- [2α, 3α-cyclohexylidenedioxy] -4-β- [N6- (2-thienylethane-2-yl) -9-adenyl] cyclopentane (0.32 g) in 2 ml of benzene to a benzene solution of potassium permanganate (0.29 g) and 18-crown-6 (0.016 g) at 0 ° C. The reaction mixture is maintained at room temperature for about 6 hours, 5% aqueous NaOH (15 ml) is added, and filter the aqueous phase through Celite®, and acidify to pH 5 with 1N HCl, and extracted with ethyl acetate. Extracts The organics are dried with MgSO4 and concentrated in vacuo to produce 0.1 g of [2α, 3α-cyclohexylidenedioxy] -4β- [N6- (2-thienylethane-2-yl) -9-adenyl] cyclopentan-1-β-carboxylate in the form of yellow oil, which dissolves in methylene chloride (4 ml) containing dicyclohexyl carbodiimide (DCC) (0.044 g). I know add ethylamine (0.4 ml) to the mixture, which is left stirring at room temperature for about 18 hours, the solvent in vacuo and the crude product is purified by flash chromatography (methylene chloride / methanol 98: 2) to produce 0.077 g of pure product.

Example 4 Preparation of N6- [trans-2- (thiophen-2-yl) cyclohex-4-en-yl] adenosine

Trans-2- (2'-thiophenyl) -cyclohex-4-enylamine (0.3 g) prepared according to the method described in Example C, above, 6-chloropurine riboside (0.28 g) and Triethylamine (0.27 ml) in 20 ml of ethanol is heated to reflux overnight in argon. The reaction mixture is cooled to RT, removes the solvent and the residue is purified by MPLC (chloroform: methanol; 95: 5), followed by vacuum drying to approximately 80 ° C, to produce the final product in the form of solid, m.p. 105-110 ° C; elemental analysis, C_20 H_ {23} N5 {4} S.

Example 5 Preparation of N6- [trans-2- (thiophen-2-yl) cyclohex-4-en-1-yl] adenosine-5'-N-ethylcarboxamide

Stage one

It reacts (+) - trans-2- (thiophen-2-yl) cyclohex-4-enylamine and the 2 ', 3'-dimethylmethylenedioxy derivative of 6-Cl-NECA in the conditions described in Example 4, to produce the derivative 2 ', 3'-dimethylmethylenedioxy of the final product.

Stage two

Derivative 2 ', 3'-dimethylmethylenedioxy of the desired product is mixture with trifluoroacetic acid / water (90/10) for 30 min at RT, it is neutralized by pouring the mixture slowly into a solution saturated with sodium bicarbonate, and extracted with methylene The aqueous layer is extracted with methylene chloride and the organic layers are combined, washed with brine, dried with magnesium sulfate and filtered, and the clear filtered solution is evaporates The residue is purified by chromatography by sudden desorption (methylene chloride: methanol 9: 1) to produce, when dried under vacuum, the final product in the form of glass foam white, m.p. 112-117 ° C; C_22 H_ {26} N6 {4} S.

Example 6 Preparation of (-) - [2S- [2α, 3α-dihydroxy-4-β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methyl ethyl] amino] - 9-adenyl] cyclopentan] -1-? -N-ethylcarboxamide

Stage one

(+) - [2S- [2α, 3α-dimethylmethylenedioxy] -4-β- (6-chloro-9-adenyl)] cyclopentan-1-β-N-ethylcarboxamide, prepared as described in Example 2, and 2'R- (5-chlorothien-2-yl) -2-propyl amine, [α] D TA = -15.6 (C. 3.7, CH 3 OH), prepared as described in Example 4, they are combined as described in Example 4, giving the derivative 2,3-dimethylmethylenedioxy of the final product.

Stage two

The dimethylmethylenedioxy derivative of Step (1) heated in 5 ml of 50% aqueous formic acid at reflux for about 3 hours. The cooled reaction mixture is evaporate, toluene is added to the solid residue, and the solvent The residue was dissolved in ethyl acetate, washed with sodium bicarbonate solution and brine, dried, filtered and evaporated to give, after drying in a stove overnight, a white solid product (0.240 g), m.p. 188-4 ° C; C 20 H 25 N 6 SO 3 Cl, [α] D TA = -86.49 (C. 5.5, MeOH).

Examples 7-33

Following the general procedures of the Examples 1 to 6 above, the compounds of the invention listed in Table 1. In examples 7 to 21, 31 and 32, the heterocyclic amine was reacted with Commercially available 6-chloropurine riboside; in Examples 22 and 23, the heterocyclic amine was reacted with N6-chloro-5'-N-ethylcarboxamidoadenosine; and in examples 24 to 30, 32 and 33, the heterocyclic amine was made react with (±) or (+) - [2S- [2α, 3α-dimethylmethylenedioxy] -4-β- (6-chloro-9-adenyl)] -cyclopentan-1-β-N-ethylcarboxamide.

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TABLE I

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TABLE I (continued)

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TABLE I (continued)

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TABLE I (continued)

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Example 34 Preparation of (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan- 1β-N-ethylcarboxamide-N 1 -oxide

A solution of 2S-2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -methyl] amino-9-adenyl] cyclopentan-1β-N-ethylcarboxamide (0.25 g) and glacial acetic acid (20 ml) in hydrogen peroxide 30% (1 L) for 4 days at room temperature, and concentrate The mixture in vacuo. The residue is purified by chromatography. by sudden desorption, eluting with 20% methanol in acetate ethyl, followed by stirring with hot methanol and filtered to give  the desired product, m.p. > 240 ° C.

Example 35 Preparation of (2S) -2α, 3α-bis-methoxycarbonyloxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan-1? -N-ethylcarboxamide

To a solution of (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan-1β-N-ethylcarboxamide (0.56 g) and triethylamine (0.5 ml) and 4-dimethylaminopyridine (1 mg) in tetrahydrofuran (25 ml) methyl chloroformate (0.21 ml) is added, and the mixture is stirred dissolution at room temperature for 1 hour. The mixture of dilute with ethyl acetate, wash with brine and dissolve Organic is dried with magnesium sulfate, filtered and concentrated at empty. The crude product is recrystallized from hexane / acetate of ethyl to give the desired product, m.p. 74-76 ° C.

Example 36 Preparation of (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan- 1β-N-ethylcarboxamide ethoxymethylene acetal

A solution of (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methyl-ethyl] amino-9-adenyl] cyclopentan-1? -N-ethylcarboxamide (0.14 g), triethylortoformate (3 ml) and acid p-toluenesulfonic acid (1 mg) is heated to reflux for about 1 hour, and then the solvent is removed by empty. The residue is dissolved in ethyl acetate and the solution with brine, dried over sodium sulfate, filtered and Concentrate in vacuo. The crude product is purified by flash chromatography, eluting with 5% methanol in methylene chloride, followed by recrystallization from hexane / ethyl acetate, to give the desired product, m.p. 67-70 ° C.

Example 37 Preparation of (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan- 1β-N-ethylcarboxamide-2,3-carbonate

A solution of (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methyl-ethyl] amino-9-adenyl] cyclopentan-1? -N-ethylcarboxamide (0.17 g) and 1,1'-carbonyldiimidazole (0.071 g) in Benzene (5 ml) is refluxed for 5 hours and then stirred at 60 ° C for about 18 hours. The solution is washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. I know  Purify the residue by flash chromatography, eluting with 5% methanol in methylene chloride, followed by crystallization from hexane / ethyl acetate to give the desired product, m.p. 87-89 ° C.

Example 38 Preparation of (2S) -2α, 3α-bis-methylcarbamoyloxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methyl ethyl] amino-9-adenyl] cyclopentan-1? -N-ethylcarboxamide

To a solution of (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan- 1β-N-ethylcarboxamide (0.16 g) in tetrahydrofuran (5 ml) is added isocyanate of methyl (0.05 ml) and 1,8-diazabicyclo [5,4,0] undec-7-eno (1 drop) The solution is stirred at 50 ° C for about 2.5 hours, cooled to room temperature, diluted with acetate ethyl and washed with brine. The organic solution is washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by flash chromatography, eluting with 5% methanol in methylene chloride, followed by crystallization from hexane / ethyl acetate to give the desired product, m.p. 97-99 ° C.

Example 39 Preparation of (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan- 1β-N-ethylcarboxamide-2,3-thiocarbonate

A solution of (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methyl-ethyl] amino-9-adenyl] cyclopentan-1? -N-ethylcarboxamide (0.35 g) and thiocarbonyldiimidazole (0.134 g) in benzene (10 ml) was heat at 45 ° C for about 2 hours. The solution is washed with brine, dried over magnesium sulfate and concentrated to empty. The residue is purified by desorption chromatography. Sudden, eluting with 5% methanol in hexane, followed by crystallization from hexane to give the desired product, m.p. 115-117 ° C.

Example 40 Preparation of N 6 - [2- (3-chloro-2-thienyl) - (1R) -1-methyl ethyl] -2'-O-methyladenosine

A solution of 6-chloro-9- (2'-O-methyl-? -D-ribofuranosyl) -9H-purine  (prepared as in EP publication No. 0378518) (0.28 g), 2- (3-Chloro-2-thienyl) - (1R) -1-methylethylamine (0.163 g) and triethylamine (0.5 ml) in ethanol (30 ml) is refluxed for about 18 hours, it is cooled and concentrated in vacuo. The residue is purified by flash chromatography, eluting with 10% methanol in methylene chloride, followed by crystallization from hexane / ethyl acetate to give the desired product, m.p. 75-76 ° C.

Example 41 Preparation of N 6 - [2- (5-chloro-2-thienyl) - (1R) -1-methyl ethyl] -2'-O-methyladenosine

Using essentially the procedure of Example 40, the desired product is prepared, m.p. 84-85 ° C, at start from 2- (5-Chloro-2-thienyl) - (1R) -1-methylethylamine.

Example 42 Preparation of N 6 - [trans-5- (2-thienyl) cyclohex-1-en-4-yl] -2'-O-methyladenosine

Using essentially the procedure of Example 40, the desired product is prepared, m.p. 86-89 ° C, at start from trans-2- (2-thienyl) cyclohex-4-enylamine.

Example 43 Preparation of 1 (R) -2- (5-chloro-2-thienyl) -1-methylethylamine

Stage one

Preparation of 1 (S) -2- (5-chloro-2-thienyl) -1-hydroxy-1-methylethane

A solution of 2-chlorothiophene (8.17 g) in tetrahydrofuran (80 ml) at -30 ° C and 1.6 M n-butyllithium is added in hexanes (43.0 ml) drop by drop. The mixture is stirred at -30 ° C for about 1 hour, (S) -propylene oxide is added (4.00 g), and the mixture is heated to 0 ° C and stirred at that temperature  for about 3 hours. Stop the reaction with solution aqueous saturated ammonium chloride, diluted with ether and separated the layers The organic layer is washed with brine, dried with magnesium sulfate and concentrated in vacuo to give the product wanted.

Stage two

Preparation of 1 (R) -2- (5-chloro-2-thienyl) -1-methyl-1-phthalimidoethane

To a solution of 1 (S) -2- (5-chloro-2-thienyl) -1-hydroxy-1-methylethane (8.8 g), triphenylphosphine (13.1 g) and phthalimide (7.35 g) in tetrahydrofuran (80 ml) is added dropwise azodicarboxylate of diethyl (7.9 ml). The solution is stirred for about 18 hours and the solvent is removed in vacuo. The residue is purified by flash chromatography, eluting with 20% of hexanes in methylene chloride, to give the desired product.

Stage 3

Preparation of 1 (R) -2- (5-chloro-2-thienyl) -1-methylethylamine

It dissolves 1 (R) -2- (5-chloro-2-thienyl) -1-methyl-1-phthalimidoethane (13.0 g) in ethanol (75 ml) and hydrazine hydrate (2.5 ml), and the mixture is stirred at reflux for about 1 hour. I know cool the mixture to room temperature, the solid is removed by filtration and the filtrate is concentrated in vacuo. The residue it is dissolved in ethyl acetate and this solution is stirred with acid  5N aqueous hydrochloric. The layers are separated and the aqueous one adjusts to pH> 10 with 10% solution of sodium hydroxide, and then extract with ethyl acetate. The organic solution is washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum to give the desired product, [α] D = -22.96 ° (c = 11.5, methanol).

Example 44 Preparation of 1 (R) -2- (2-thienyl) -1-methylethylamine

Stage one

Preparation of 1 (S) -2- (2-thienyl) -1-hydroxy-1-methylethane

Using essentially the procedure of Example 50, Step 1, the desired product is prepared from thiophene

Stage two

Preparation of 1 (R) -2- (2-thienyl) -1-methyl-1-phthalimidoethane

Using essentially the procedure of Example 50, Step 2, the desired product is prepared from 1 (S) -2- (2-thienyl) -1-hydroxy-1-methylethane.

Stage 3

Preparation of 1 (R) -2- (2-thienyl) -1-methylethylamine

Using essentially the procedure of Example 50, Step 3, the desired product [α] D is prepared = -15.6º (c = 1, methanol) from 1 (R) -2- (2-thienyl) -1-methyl-1-phthalimidoethane.

Example 45 Preparation of 1 (S) -2- (5-chloro-2-thienyl) -1-methylethylamine

Stage one

Preparation of 1 (S) -2- (5-chloro-2-thienyl) -1-hydroxy-1-methylethane

To a stirred solution of 1 (S) -2- (5-chloro-2-thienyl) -1-hydroxy-1-methylethane (5.70 g) in tetrahydrofuran (100 ml) triphenylphosphine is added (5.34 g) and benzoic acid (2.49 g). Azodicarboxylate of diethyl (3.22 ml) dropwise, and the mixture is stirred at temperature ambient for 18 hours. The solvent is removed in vacuo. The residue is purified by flash chromatography, eluting with 30% hexanes in methylene chloride, to give benzoate (R) -3- (5-Chloro-2-thienyl) -2-propyl. The ester (3.91 g) is dissolved in dioxane (50 ml) and added 20% aqueous sodium hydroxide (15 ml). The mixture is heated to 55 ° C for 3 hours and concentrated in vacuo. The residue is absorbed in ethyl acetate (200 ml) and the organic layer is washed with brine, dried over magnesium sulfate, filtered and concentrated at  empty to give the desired product.

Stage two

Preparation of 1 (S) -2- (5-chloro-2-thienyl) -1-methylethylamine

Using essentially the procedure of Example 50, steps 2 and 3, the desired product is prepared, [α] D = + 21.71 ° (c = 1.1, methanol) from 1 (S) -2- (5-chloro-2-thienyl) -1-hydroxy-1-methylethane.

Using essentially the procedures of the Examples 43, 44 and 45, the following compounds are prepared to from appropriate starting materials.

Example 46 1 (R) -2- (benzothiophene-2-yl) -1-methylethylamine Example 47 1 (S) -2- (2-thienyl) -1-methylethylamine, α D = 15.5 ° (c = 1, methanol) Example 48 1 (R) -2- (3-bromo-2-thienyl) -1-methylethylamine Example 49 1 (R) -2- [5- (2-pyridyl) -2-thienyl] -1-methylethylamine Example 50 1 (R) -2- [5- (2-thienyl) -2-thienyl] -1-methylethylamine Example 51 1 (R) -2- (5-phenyl-2-thienyl) -1-methylethylamine Example 52 1 (R) -2- (5-methoxy-2-thienyl) -1-methylethylamine Example 53 1 (R) -2- (5-methyl-2-thienyl) -1-methylethylamine Example 54 1 (R) -2- (5-bromo-2-thienyl) -1-methylethylamine Example 55 1 (R) -2- (5-iodo-2-thienyl) -1-methylethylamine

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Example 56 1 (R) -2- (5-methylthio-2-thienyl) -1-methylethylamine Example 57 1 (R) -2- (5-methylsulfonyl-2-thienyl) -1-methylethylamine Example 58 1 (R) -2- (5-ethyl-2-thienyl) -1-methylethylamine Example 59 1 (R) -2- [5-n-heptyl-2-thienyl) -1-methylethylamine Example 60 1 (R) -2- (3-methyl-2-thienyl) -1-methylethylamine Example 61 1 (R) -2- (4-methyl-2-thienyl) -1-methylethylamine Example 62 1 (R) -2- (3-Chloro-2-thienyl) -1-methylethylamine, [α] D = -6.1 ° (c = 1, methanol) Example 63 1 (R) -2- (4-chloro-2-thienyl) -1-methylethylamine Example 64 1 (R) -2- (3-Chloro-5-phenyl-2-thienyl) -1-methylethylamine Example 65 1 (R) -2- (5-bromo-2-chloro-2-thienyl) -1-methylethylamine Example 66 1 (R) -2- (4-methyl-5-chloro-2-thienyl) -1-methylethylamine Example 67 1 (R) -2- (2,5-dichloro-3-thienyl) -1-methylethylamine

The compounds of the present invention are useful for the prevention or reduction of myocardial injury consequent to myocardial ischemia; and also act as antilipolytic agents useful for reducing lipid levels, triglyceride levels or cholesterol levels in the treatment of hyperlipidemia and hypercholesterolemia.

Compounds within the scope of this invention exhibit activity in receptor binding assays A_ {1} / A_ {standard} for the determination of the activity of adenosine receptor agonist in mammals. The procedures test specimens that are useful for determining the affinity of receptor binding of the compounds of the present invention is described later.

A. Determination of affinity of adenosine receptor binding in vitro

Receptor binding affinity A 1 was determined by competitive assay based on the displacement of ligand 3 H-CHA (cyclohexyl adenosine) [Research Biochemicals Inc., Natick, Mass.] Of the receptor, using a preparation of Rat whole brain membrane, according to RF procedure Bruns et al ., Mol Pharmacol., 29: 331 (1986). Nonspecific binding was evaluated in the presence of 1 mM theophylline.

The binding affinity to A2 receptor is determined by a similar test technique, based on the displacement of ligand3 H-CGS 21680, a known agonist of A 2 receptor-specific adenosine, of receptor, using striatum membranes of rat brain. Nonspecific binding was evaluated in the presence of 20 µM 2-chloroadenosine.

The tests were carried out in test tubes of glass in duplicate at 25 ° C. Once the membranes, the tubes were vortexed and incubated at 25 ° C for 60 minutes (A 1 test) or 90 minutes (A 2 test) on a rotary shaker. The test tubes were vortexed in the middle of the incubation, and again almost at the end. Rehearsals are they ended by rapid filtration through GF / B filters of 2.4 cm using a Brandel Cell Harvestor. The tubes were washed three times test with 50 mM tris-HCl (pH 7.7 or 7.4), the filtration being completed in 15 seconds. The filters wet ones were placed in glass scintillation vials filled with 10 ml of Aquasol II (New England Nuclear). They left stirring the vials overnight on a rotary shaker and placed in a liquid scintillation analyzer during counts of two minutes The IC 50 values for receptor binding, is that is, the concentration at which a compound of the invention shifted the radiolabeled standard, were obtained using a program of curve adjustment computer (RS / 1, Bolt, Beranek and Newman, Boston, MA).

B. Determination of in vitro vasorelaxation in isolated coronary pig arteries

Coronary pig arteries were obtained from a local slaughterhouse, they were carefully dissected and cleaned of grease, blood and adherent tissue. Rings of approximately 2-3 mm wide and transferred to tissue baths  with water jacket (10 ml) filled with buffer Krebs-Henseleit hot (37ºC) and oxygenated (O 2 / CO 2: 95% / 5%), and were mounted on L-hooks between Stainless steel rods and a force transducer. The Krebs buffer composition is as follows (mM): NaCl, 118; KCl, 4.7; CaCl2, 2.5; MgSO 4, 1.2; KH 2 PO 4, 1.2; NaHCO 3, 25.0; and glucose, 10.0. The rings balanced for 90 minutes with frequent buffer changes in a tension resting 5 g. To ensure optimal tension development, the  arterial rings were primed twice with 36 mM KCl and once with 10 µM PGF2α, before exposing them to PGF2α3 µM. When the isometric voltage had reached a state constant, cumulative doses of agonists of adenosine of the invention (usually 1 mM to 100 µM, in stockings logarithmic units) to the bathrooms. The tension achieved with PGF2α3 µM was considered equivalent to 100%; the others values were expressed as a percentage of that maximum. The values of IC 50 for relaxation, that is, the concentration at which a compound of the invention caused a 50% reduction in the voltage was determined using the adjustment computer program of linear curves mentioned above.

C. In vivo determinations of mean blood pressure (TAM) and heart rate (HR) in anesthetized and spontaneously hypertensive normotensive rat 1. Anesthetized rats

Normotensive rats were anesthetized with sodium pentobarbital (50 mg / kg, i.p.) and placed on a table Heated surgical. Cannulas were inserted into the artery and vein femoral to allow measurement of blood pressure and facilitate intravenous administration of test compounds. Left that the animals were balanced for 10 minutes after surgery. The mean blood pressure was measured continuously and recorded, and the heart rate was monitored using the pulse of the blood pressure to operate a cardiotachometer. After establish and record the reference parameters, it administered intravenously increasing doses (1, 3, 10, 30, 100, 300 and 1000 µg / kg) of the compound of the invention to be tested. I know observed maximum changes in cardiovascular parameters after each dose of the adenosine agonist. Only one was administered composed of rat. The potency of the compounds to decrease the heart rate and mean blood pressure was assessed by determining the dose of the agent necessary to decrease the heart rate or the blood pressure 25% (DE 25).

2. Spontaneously hypertensive rat (REH)

The oral antihypertensive activity of Compounds of the invention were examined in rats spontaneously conscious hypertensive. The rats were anesthetized with sodium pentobarbital (50 mg / kg i.p.). It was implanted in the abdomen of the rats a telemetric transducer by means of an incision in the middle line. The transducer cannula was inserted into the aorta abdominal to allow direct measurement of blood pressure in the conscious REH. The transducer was secured to the abdominal wall. After recovering from surgery (minimum of seven days), REHs will placed on a receiver board and the transducer / transmitter is active. Systolic, diastolic and blood pressure were recorded. mean and heart rate for 1.5 hours in the conscious rat Free to establish a stable reference. After each rat received a single dose of the compound of the invention to be tested, or vehicle, and changes in the blood pressure and heart rate for 20 hours.

Table II presents the results of the biological activity determinations for the compounds copies, and for the compound of Example 6, Step 1, within scope of the invention.

TABLE II

24

TABLE II (continued)

25

When blood flow is interrupted at heart for short periods of time (2 to 5 minutes), followed of restoration of blood flow (reperfusion), the heart It protects against the development of injury when blood flow it is interrupted for longer periods of time (for example, 30 minutes).

The compounds of the invention exhibit activity in the tests used to determine the capacity of the compounds to mimic the cardioprotective activity of preconditioning myocardial Exemplary test procedures that are useful to determine the cardioprotective activity of the compounds of The present invention is described below.

Determination of cardioprotective activity in rat 1. General surgical preparation

Rats are anesthetized Adult Sprague-Dawley with Inactin (100 mg / kg i.p.). The trachea is piped and pressure ventilation is provided positive through a small animal respirator. I know placed catheters in the vein and femoral artery for administration of the compounds of the present invention to be tested and for the measurement of blood pressure, respectively. It does an incision on the left side of the chest over the muscles pectorals, and the muscles are removed to expose the room intercostal space The thoracic cavity is opened and the heart. A piece of proline suture is placed 4-0 through the ventricular wall near the left main coronary artery, and is used to disrupt the blood flow through the coronary artery tightening a knot sliding. A pulsed Doppler flow probe (a device that measures blood flow) on the surface of the heart to confirm that the coronary artery has been identified correctly. A catheter is also placed in the ventricle left to monitor left ventricular function during the experiment.

2. Preconditioning and testing procedures

To precondition the heart, the coronary artery (flow is interrupted) for a period of two minutes Then the slip knot is loosened to restore the flow (reperfusion) over a period of three minutes. East Occlusion / reperfusion procedure is repeated twice. Five minutes after the conclusion of the final preconditioning, it reocludes the artery for 30 minutes, followed by reperfusion for three hours When you are going to test a compound of the present invention, instead of performing the procedure of occlusion / reperfusion, the compound is infused for 30 minutes before the occlusion period of 30 minutes. At the end of the period of reperfusion of 3 hours, the artery is reoccluded and administered 1 ml Patented Blue dye in the left ventricular catheter, and the heart is stopped by administration i.v. of chloride potassium This procedure allows the dye to perfuse the normal areas of the heart while the part of the heart that made ischemic does not absorb the dye (this is the area at risk, the "risk area"). The heart is quickly removed for infarct size analysis. The size of the infarction is determined cutting the heart from the tip to the base in four or five 1-2 mm wide slices. The slices are incubated in a solution of 1% triphenyltetrazolium for 15 minutes. This staining reacts with the viable tissue and causes it to develop A brick red color. The infarcted tissue does not react with the staining and is pale white in appearance. The tissue slices are placed in a video image analysis system and it determines the size of the infarction by planimetry. The effect of the compound of the present invention tested on the size of myocardial infarction and is used to quantify the scope of cardioprotective activity. The results are given as the percentage of the risk area that is infarcted.

The results of a compound test exemplary within the scope of the present invention by means of Previous methods are given in Table III below.

TABLE III

Group of animals % of risk area infarcted Control1 63 ± 5 Preconditioned2 15 ± 8 Compound under 3 23 ± 9 Compound high 4 18 ± 5 1 Unconditioned animals or treated with the compound. 2 Animals preconditioned by occlusion / reperfusion procedure.  \ begin {minipage} [T] {150mm} 3 Animals received rapid injection i.v. 1 µg / kg, followed by infusion i.v. 0.1 µg / kg / minute for 30 minutes before the 30 minute occlusion period of the compound of Example 39. \ end {minipage}  \ begin {minipage} [T] {150mm} ^ {4} Animals they received rapid injection i.v. 10 µg / kg, followed by infusion i.v. 1 µg / kg / minute from 30 minutes before 30-minute occlusion period, up to 2 hours after the start of reperfusion, of the compound of Example 39. \ end {minipage}

The compounds of the present invention exhibit activity in the trials used to determine the capacity of the compounds to inhibit lipolysis. Test procedures copies that are useful for determining activity Antilipolytic compounds of the present invention are described later.

Determination of antilipolytic activity in adipocytes of rat 1. Isolation of epididymal fat adipocytes

Adipose tissue is removed from anesthetized rats and washed twice in incubation medium (2.09 g of bicarbonate sodium and 0.04 g of EDTA, disodium salt, in 1 L of Krebs buffer). Each rat (300-350 g) produces approximately 4 ml of adipose tissue. Adipose tissue (35 ml) is cut with scissors in small pieces and washed with incubation medium (50 ml). The mixture is poured into the cylinder of a 50 ml syringe to which a short piece of tubing attached with a clamp is attached instead needle The aqueous phase is allowed to drain. One second goes by washing with incubation medium through the syringe. The tissue at 50 ml of collagenase solution (collagenase (90 mg), Bovine serum albumin (BSA) (500 mg) and chloride solution 0.1 M calcium (1 ml) in incubation medium (50 ml) in a bottle of 1 L. The mixture is stirred in an incubator at 37 ° C for around 60 minutes in an atmosphere of 95% oxygen / 5% carbon dioxide to carry out tissue digestion. Scattered cells they are poured through two layers of cheesecloth into a glass of 100 ml plastic precipitates. The undigested lumps of the Cloth are washed once with incubation medium (20 ml). I know centrifuge the beaker cells in 2 tubes of plastic for 30 seconds at room temperature at 300 rpm. I know aspirates the aqueous phase from under the poorly compact cell layer of floating grease and discarded. Adipocytes are spilled little to bit in a 250 ml plastic beaker containing 100 ml of wash solution (1 g of BSA per 100 ml of incubation). After gentle agitation, the stage of centrifugation It is followed by another wash with washing solution. I know Mix the cells and estimate their volume with a graduated cylinder.  The adipocytes are diluted in twice their buffer volume. Assay (incubation medium (120 ml), BSA (1.2 g), pyruvic acid (13 mg)).

2. In vitro lipolysis assay

The test is performed in scintillation vials of 20 ml plastic, and the total test volume is 4.2 ml. I know incubate assay buffer (2.5 ml), diluted adipocytes (1.5 ml) and a solution of the compound to be tested (12.3 µl) of agonist of adenosine (12.3 µl; variable concentration) in the agitator incubator for 15 minutes, and then the reaction starts with norepinephrine solution (41.2 µl) (10 nM, in a solution vehicle containing water (100 ml), BSA (4 mg) and 0.1 M EDTA (20 µ)) and adenosine deaminase (1 µg / ml, 41.2 µ). After sixty minutes on the stirrer, the reaction is terminated by putting the Ice vials The content of each vial is transferred to a tube 12x75 mm glass and centrifuged at 8-10 ° C at 3600 rpm for 20 min. The hard lipid layer is removed by aspiration, and glycerol in the aqueous layer is analyzed (400 µl shows). Positive control is done in the absence of agonist of adenosine, replacing with water instead of dissolving a test.

The results of testing the compounds of the present invention are given in Table IV, below, and are report as% inhibition of glycerol production of 1 µM and / or 0.1 µM compound tested for control positive and as EC50 values, that is, the concentration of tested compound necessary to carry out an inhibition of 50% of glycerol production. For comparison purposes, also the results for the compounds of the literature are given N-cyclopentyladenosine (CPA), N-ethylcarboxamidoadenosine (NECA), R-phenylisopropyladenosine (R-PIA) and 2 - [[2- [4 - [(2-carboxethyl) phenyl] ethyl] amino] -N-ethylcarboxamidoadenosine  (CGS21680).

TABLE IV

Compound of the  \ hskip0,9cm% of inhibition Example No. one \ muM 0.1 µM CE_ {50} 6 0.76 nM 26 96 89 nM 31 0.26 p.m 39 5.4 nM 41 88 46 4 nM 47 94 0.63 nM 48 88 1.86 nM 49 85 18.6 nM CPA 100 97 0.31 nM NECA 2.5 nM R-PIA one nM CGS21680 0

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The receptor binding activity A1 and A 2 of adenosine and vasorelaxation for the compounds of the Table IV bibliography, as determined by the methods described above, are given in Table V, below.

TABLE V

Union to receiver of adenosine (IC 50) Vasorelation Compound A_ {1} (nM) A_ {2} (nM) (IC 50) CPA 0.72 1584 3.18 NECA 12 17 0.017 R-PIA 2.4 300 0.76 CGS21680 30000 70 0.08

The antilipolytic activity of adenosine is mediated through activation of the A1 receptor subtype. Selective agonists of the A2 receptor subtype, such like CGS 21680, they do not exhibit antilipolytic activity. In consequently, although certain selective agonists of A 1 may have no desirable antihypertensive activity and agonists of A2 may not be effective antilipolytic agents, the Compounds of the present invention that are mixed agonists are incomparably convenient to effectively treat two risk factors discussed above, that is, the hypertension and hyperlipidemia.

The compounds of this invention are usually can be administered orally or parenterally, in the treatment of patients suffering from hypertension, myocardial ischemia or in patients who need cardioprotective therapy or therapy antilipolytic As used here, the term "patients" It includes humans and other mammals.

The compounds of this invention, preferably in salt form, they can be formulated for administration in in any convenient way, and the invention includes within its reach pharmaceutical compositions containing at least one compound according to the invention adapted for use in human medicine or veterinary Such compositions can be formulated in a manner conventional using one or more vehicles or excipients pharmaceutically acceptable. Suitable vehicles include solvents or fillers, sterile and various aqueous media non-toxic organic solvents The compositions can be formulated in the form of tablets, capsules, pills, troches, candies hard, powders, suspensions or aqueous solutions, solutions injectables, elixirs, syrups and the like, and may contain one or more agents selected from the group that includes agents sweeteners, flavoring agents, coloring agents and agents preservatives, to provide a pharmaceutical preparation acceptable.

The private vehicle and the proportion of Adenosine agonists with respect to the vehicle are determined by the solubility and chemical properties of the compounds, the mode particular administration and pharmaceutical practice normalized For example, to produce tablets can be used excipients such as lactose, sodium citrate, calcium carbonate and bicalcium phosphate and various disintegrants such as starch, alginic acid and certain complex silicates, together with agents lubricants such as magnesium stearate, sodium lauryl sulfate and talcum powder. For a capsule form, they are among the vehicles preferred pharmaceutically acceptable lactose and high molecular weight polyethylene glycols. When they are formulated aqueous suspensions for oral use, the vehicle may be agents emulsifiers or suspension. Such solvents can be used such as ethanol, propylene glycol, glycerin and chloroform and their combinations, as well as other materials.

For parenteral administration, they can be used solutions or suspensions of these compounds in sesame oil or peanut, or aqueous propylene glycol solutions, as well as sterile aqueous solutions of soluble salts Pharmaceutically acceptable described here. The solutions of the salts of these compounds are especially suitable for administration by intramuscular and subcutaneous injection. The aqueous solutions, which include those of salts dissolved in pure distilled water, are suitable for administration by intravenous injection, as long as its pH is adjusted properly, and that they are properly buffered, made isotonic with sufficient saline or glucose, and sterilized by heating or by microfiltration

The dosage regimen used to carry The methods of this invention are those that ensure maximum therapeutic response until improvement is obtained, and then the minimum effective level that gives relief. So, in general, the Dosages are those that are therapeutically effective for lower blood pressure in the treatment of hypertension, to increase coronary blood flow in the treatment of myocardial ischemia, to produce a cardioprotective effect, is that is, the improvement of the ischemic lesion or the size of the infarction of myocardium resulting from myocardial ischemia, or to produce a antilipolytic effect In general, the oral dose may be between about 0.1 and about 100 (preferably in the range of 1 to 10 mg / kg), and the dose i.v. around 0.01 a about 10 mg / kg (preferably in the range of 0.1 to 5 mg / kg), taking into account, of course, that when selecting the Appropriate dosage in any specific case is due consider the patient's weight, general health, age and others factors that can influence the response to the drug.

The compounds of the invention can be administer as frequently as necessary to achieve and maintain the desired therapeutic response. Some patients may respond quickly to a relatively large or small dose and They need little or no maintenance dosage. For other On the other hand, other patients may need sustained dosing of about 1 to about 4 times a day, depending on the physiological needs of the particular patient. Normally the drug can be administered orally about 1 to around 4 times a day. It is anticipated that many patients will not need more than about one to about two doses daily.

It is also anticipated that the present invention it would be useful as an injectable dosage form that can be administer a patient suffering from hypertension in an emergency acute or myocardial ischemia, or a patient who needs cardioprotection or antilipolytic therapy. Such treatment can go followed by intravenous infusion of the active compound, and the amount of compound infused in such a patient should be effective for achieve and maintain the desired therapeutic response.

Claims (15)

1. The use of a compound of formula 26 in the what: K is N or N? Q is CH2 or O; T is 27 or R 3 O-CH 2; X is a C1-C20 alkylene of linear or branched chain, or carbocyclic group C4-C8 1,2 or 1,3-bivalent, each of which is optionally substituted by at least one CH 3, CH 3 CH 2, Cl, F, CF 3 or CH 3 O; Y is NR4, O or S; a = 0 or 1; Z is of formula 28 ; Z_ {1} is N, CR_ {5}, (CH) m -CR5 or (CH) m -N, with m 1 or 2; Z 2 is N, NR 6, O or S, with n 0 or one; R1, R2, R3, R4, R5 and R 6 are independently H, C1-C20 alkyl, phenyl unsubstituted or substituted with one or more substituents selected from C1-C20 alkyl, alkoxy C1-C20, amino, nitro, carboxyl, carboalkoxy C1-C20, cyano, C1-C20 alkyl amino, halo, hydroxy, C1-C20 hydroxyalkyl, mercapto, C1-C20 alkyl mercapto, carbalquil C1-C20 and carbamoyl, or heterocyclyl 4 to 10 members in which one or more ring atoms are N, O or S, in the that said heterocyclyl ring is unsubstituted, or substituted with one or more substituents selected from alkoxy C1-C20, C1-C20 alkyl amino, phenyl, C1-C20 carbalkyl, carbamoyl, cyano, halo, hydroxy, mercapto, C1-C20 alkyl mercapto and nitro; R_a and R_b are independently H, OH, C1-C20 alkyl, hydroxyalkyl C1-C20, C1-C20 alkyl mercapto, C1-C20 thioalkyl, C1-C20 alkoxy, C1-C20 alkyloxy C1-C20 alkyl, amino, C1-C20 alkylamino, carboxyl, acyl C1-C6, halogen carbamoyl, carbamoyl C1-C20 alkyl, unsubstituted or substituted phenyl with one or more substituents selected from alkyl C1-C20, C1-C20 alkoxy, amino, nitro, carboxyl, C1-C20 carboalkoxy, cyano, alkyl C1-C20 amino, halo, hydroxy, hydroxyalkyl C1-C20, mercapto, C1-C20 alkyl mercapto, C1-C20 carbalkyl and carbamoyl, or 4 to 10-membered heterocyclyl, in which one or more atoms of the ring are N, O or S, wherein said heterocyclyl ring is without replace or substituted with one or more substituents selected from C1-C20 alkoxy, C1-C20 alkyl amino, phenyl, C1-C20 carbalkyl, carbamoyl, cyano, halo, hydroxy, mercapto, C1-C20 alkyl mercapto and nitro; Y R 'and R' 'are independently hydrogen, C1-C20 alkyl, C1-C20 phenylalkyl, carbamoyl, C1-C20 alkyl carbamoyl, dialkyl C1-C20 carbamoyl, C1-C6 acyl, C1-C20 alkyloxycarbonyl, phenylalkoxycarbonyl C1-C20, or phenyloxycarbonyl, wherein said ring phenyl is unsubstituted or substituted with one or more substituents selected from C1-C20 alkyl, alkoxy C1-C20, amino, nitro, carboxy, carbalkyl C1-C20, cyano, C1-C20 alkyl amino, halo, hydroxy, C1-C20 hydroxyalkyl, mercapto, C1-C20 alkyl mercapto, carbalkyl C1-C20 and carbamoyl, or R 'and R' 'can form together 29 wherein R c is hydrogen or C1-C20 alkyl, 30 wherein R d and R e are independently hydrogen, C1-C20 alkyl, or together with the carbon atom to which they are attached can form a 1,1-cycloalkyl group; provided that when X is alkylene C1-C20 linear chain and Q is oxygen, Z represents a heterocyclyl that includes at least two heteroatoms; or its pharmaceutically acceptable salt, in the preparation of a medicament for use in the prevention of injury ischemic 2. The use of the compound according to claim 1, in which R 'and R' 'are H. 3. The use of the compound according to claim 2, in which X is a C1-C6 alkylene C1-C20 optionally substituted by at least one CH 3, CH 3 CH 2, Cl, F, CF 3 or CH 3 O. 4. The use of the compound according to claim 2, in which Z is 31 5. The use of the compound according to claim 2, in which Z is a substituted or not substituted thiazolyl group, or a group benzothiazolyl substituted or not. 6. The use of the compound according to claim 4, in which X represents the alkylene fraction C1-C20 CR 9 H-CH 2, in which R 9 is hydrogen, C1-C6 alkyl, halo, C1-C6 haloalkyl or alkoxy C1-C6. 7. The use of the compound according to claim 6, in which the carbon of the C1-C20 alkylene to which is attached R 9 is a chiral center. 8. The use of the compound according to claim 7, in which R 9 is methyl or ethyl. 9. The use of the compound according to claim 7, wherein said chiral center is substantially exclusively R. 10. The use of the compound according to claim 1, in which: K is N; Q is CH2; and T is R 1 R 2 N-C = O. 11. The use of the compound according to claim 2, in which the compound is N 6 - [trans-2- (thiophen-2-yl) cyclohex-4-en-1-yl] adenosine, N 6 - [trans-2- (thiophen-3-yl) -cyclohex-4-en-1-yl] adenosine, N 6 - [2- (2'-aminobenzothiazolyl) ethyl] adenosine, N 6 - [2- (2'-thiobenzothiazolyl) ethyl] adenosine, N 6 - [2- (6'-ethoxy-2'-thiobenzothiazolyl) ethyl] adenosine, N 6 - [2- (4'-methylthiazol-5'-yl) ethyl] adenosine, N 6 - [2- (2'-thiazolyl) ethyl] adenosine, N 6 - [2- (4'-phenyl-2'-thiazolyl) ethyl] adenosine, N 6 - [(4'-phenyl-2'-thiazolyl) methyl] adenosine, N 6 - [2- (4'-methyl-2'-thiazolyl) ethyl] adenosine, N 6 - [2- (2'-methyl-4'-thiazolyl) ethyl] adenosine, N 6 - [(R) -1-methyl-2- (2'-benzo- [b] -thiophenyl) ethyl] adenosine, (-) - [2S- [2α, 3α-dihydroxy-4β- [N 6 - [2- (3-chloro-2-thienyl) -1 (R) -1-ethylethyl ] amino] -9-adenyl] cyclopentan] -1β-ethylcarboxamide, N 6 - [trans-2- (thiophen-2-yl) cyclohex-4-en-1-yl] adenosin-5'-N-ethylcarboxamide, N 6 - [2- (2'-aminobenzothiazolyl) ethyl] adenosine-5'-N-ethylcarboxamide, N 6 - [(R) -1- (5'-chlorothien-2'-yl) -2-propyl] adenosine-5'-N-ethylcarboxamide, N 6 - [(R) -1 - ((thiazo-2-yl) prop-2-yl)] adenosin-5'-N-ethylcarboxamide, N 6 - [1- (thiophen-2-yl) -2-methyl-2-propyl] adenosine-5'-N-ethylcarboxamide, N 6 - [2- (4 '' - methyl-5 '' - thiazolyl) ethyl] adenosine carbocyclic-5'-N-ethylcarboxamide, N 6 - [2- (2'-aminobenzothiazolyl) ethyl] adenosine carbocyclic-5'-N-ethylcarboxamide, N 6 - [2- (2 '' - thiazolyl) ethyl] adenosine carbocyclic-5'-N-ethylcarboxamide, (-) - [2S- [2α, 3α-dihydroxy-4β- [N 6 - [2- (5-chloro-2-thienyl) -1-methylethyl] amino] -9 -adenyl] cyclopentan] -1β-N-ethylcarboxamide, N 6 - [1- (thiophen-2 '' - il) ethan-2-yl] adenosine carbocyclic-5'-N-ethylcarboxamide, N 6 - [1- (thiophen-3-yl) ethan-2-yl] adenosine carbocyclic-5'-N-ethylcarboxamide, N 6 - [(R) -1 - ((thiophen-2-yl) prop-2-yl)] adenosine carbocyclic-5'-N-ethylcarboxamide, N 6 - [(R) -1- (5 '' - chlorothien-2-yl) -2-butyl] adenosine carbocyclic-5'-N-ethylcarboxamide, (-) - [(2S) - [2α, 3α-dihydroxy-4β- [N 6 - [2- (5-chloro-2-thienyl) - (1R) -1- methylethyl] amino-9-adenyl] cyclopentan] -1β-N-ethylcarboxamide, (2S) -2α, 3α-dihydroxy-4β- [N6- [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9-adenyl] cyclopentan-1β-N-ethylcarboxamide-N 1 -oxide, or its pharmaceutically acceptable salt. 12. The use according to claim 1, wherein the compound is N 6 - [2- (3-Chloro-2-thienyl) - (1R) -1-methylethyl] -2'-O-methyladenosine, N 6 - [2- (5-chloro-2-thienyl) - (1 R) -1-methyl ethyl] -2'-O-methyladenosine, N 6 - [trans-5- (2-thienyl) cyclohex-1-en-4-yl] -2'-O-methyladenosine, (2S) -2α, 3α-bis-methoxycarbonyloxy-4β- [N 6 - [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino- 9-adenyl] cyclopentan-1β-N-ethylcarboxamide, (2S) -2α, 3α-dihydroxy-4β- [N6 - [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9- adenyl] cyclopentan-1β-N-ethylcarboxamide  ethoxymethylene acetal, (2S) -2α, 3α-dihydroxy-4β- [N6 - [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9- adenyl] cyclopentan-1β-N-ethylcarboxamide-2,3-carbonate, (2S) -2α, 3α-bis-methylcarbamoyloxy-4β- [N 6 - [2- (5-chloro-2-thienyl) - (1R) -1-methyl ethyl] amino- 9-adenyl] cyclopentan-1β-N-ethylcarboxamide, or (2S) -2α, 3α-dihydroxy-4β- [N6 - [2- (5-chloro-2-thienyl) - (1R) -1-methylethyl] amino-9- adenyl] cyclopentan-1β-N-ethylcarboxamide-2,3-thiocarbonate, or its pharmaceutically acceptable salt. 13. The use of a compound of claim 1 or its pharmaceutically acceptable salt, in the preparation of a medication to reduce lipid levels, levels of triglycerides or cholesterol levels in a mammal. 14. The use of the compound according to claim 1, in which the compound is (-) - [2S- [2α, 3α-dihydroxy-4β- [N 6 - [2- (5-chloro-2-thienyl)] - (1R) -1-Methylethyl] amino-9-adenyl] cyclopentan] -1β-N-ethylcarboxamide, or its pharmaceutically acceptable salt. 15. The use of a compound of claim 1 or its pharmaceutically acceptable salt, in the preparation of a medicine to treat hyperlipidemia or hypercholesterolemia.